Skip to main content

Advertisement

SpringerLink
Log in

The Multiple Functions of HB-EGF in Female Reproduction and Related Cancer: Molecular Mechanisms and Targeting Strategies

  • Reproductive Biology: Review
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

Heparin-binding growth factor (HB-EGF) is a member of the epidermal growth factor (EGF) ligand family which has a crucial role in women’s health. However, there is a lack of comprehensive review to summarize the significance of HB-EGF. Therefore, this work first described the expression patterns of HB-EGF in the endometrium and ovary of different species and gestational time. Then, the focus was on exploring how it promotes the successful implantation and regulates the process of decidualization and the function of ovarian granulosa cells as an intermediate molecule. Otherwise, we also focused on the clinical and prognostic significance of HB-EGF in female-related cancers (including ovarian cancer, cervical cancer, and endometrial cancer) and breast cancer. Lastly, the article also summarizes the current drugs targeting HB-EGF in the treatment of ovarian cancer and breast cancer. Overall, these studies found that the expression of HB-EGF in the endometrium is spatiotemporal and species-specific. And it mediates the dialogue between the blastocyst and endometrium, promoting synchronous development of the blastocyst and endometrium as an intermediate molecule. HB-EGF may serve as a potentially valuable prognostic clinical indicator in tumors. And the specific inhibitor of HB-EGF (CRM197) has a certain anti-tumor ability, which can exert synergistic anti-tumor effects with conventional chemotherapy drugs. However, it also suggests that more research is needed in the future to elucidate its specific mechanisms and to accommodate clinical studies with a larger sample size to clarify its clinical value.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data Availability

Not applicable.

Code Availability

Not applicable.

References

  1. Higashiyama S, Abraham JA, Miller J, Fiddes JC, Klagsbrun M. A heparin-binding growth factor secreted by macrophage-like cells that is related to EGF. Science. 1991;251(4996):936–9.

    Article  ADS  CAS  PubMed  Google Scholar 

  2. Thompson SA, Higashiyama S, Wood K, Pollitt NS, Damm D, McEnroe G, Garrick B, Ashton N, Lau K, Hancock N, et al. Characterization of sequences within heparin-binding EGF-like growth factor that mediate interaction with heparin. J Biol Chem. 1994;269(4):2541–9.

    Article  CAS  PubMed  Google Scholar 

  3. Earp HS, Dawson TL, Li X, Yu H. Heterodimerization and functional interaction between EGF receptor family members: a new signaling paradigm with implications for breast cancer research. Breast Cancer Res Treat. 1995;35(1):115–32.

    Article  CAS  PubMed  Google Scholar 

  4. Plowman GD, Whitney GS, Neubauer MG, Green JM, McDonald VL, Todaro GJ, Shoyab M. Molecular cloning and expression of an additional epidermal growth factor receptor-related gene. Proc Natl Acad Sci U S A. 1990;87(13):4905–9.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  5. Plowman GD, Culouscou JM, Whitney GS, Green JM, Carlton GW, Foy L, Neubauer MG, Shoyab M. Ligand-specific activation of HER4/p180erbB4, a fourth member of the epidermal growth factor receptor family. Proc Natl Acad Sci U S A. 1993;90(5):1746–50.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  6. Higashiyama S, Lau K, Besner GE, Abraham JA, Klagsbrun M. Structure of heparin-binding EGF-like growth factor. Multiple forms, primary structure, and glycosylation of the mature protein. J Biol Chem. 1992;267(9):6205–12.

    Article  CAS  PubMed  Google Scholar 

  7. Elenius K, Paul S, Allison G, Sun J, Klagsbrun M. Activation of HER4 by heparin-binding EGF-like growth factor stimulates chemotaxis but not proliferation. EMBO J. 1997;16(6):1268–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Elenius K, Corfas G, Paul S, Choi CJ, Rio C, Plowman GD, Klagsbrun M. A novel juxtamembrane domain isoform of HER4/ErbB4. Isoform-specific tissue distribution and differential processing in response to phorbol ester. J Biol Chem. 1997;272(42):26761–8.

    Article  CAS  PubMed  Google Scholar 

  9. Carraway KL 3rd, Cantley LC. A neu acquaintance for erbB3 and erbB4: a role for receptor heterodimerization in growth signaling. Cell. 1994;78(1):5–8.

    Article  CAS  PubMed  Google Scholar 

  10. Higashiyama S, Abraham JA, Klagsbrun M. Heparin-binding EGF-like growth factor stimulation of smooth muscle cell migration: dependence on interactions with cell surface heparan sulfate. J Cell Biol. 1993;122(4):933–40.

    Article  CAS  PubMed  Google Scholar 

  11. Shishido Y, Sharma KD, Higashiyama S, Klagsbrun M, Mekada E. Heparin-like molecules on the cell surface potentiate binding of diphtheria toxin to the diphtheria toxin receptor/membrane-anchored heparin-binding epidermal growth factor-like growth factor. J Biol Chem. 1995;270(49):29578–85.

    Article  CAS  PubMed  Google Scholar 

  12. Aviezer D, Yayon A. Heparin-dependent binding and autophosphorylation of epidermal growth factor (EGF) receptor by heparin-binding EGF-like growth factor but not by EGF. Proc Natl Acad Sci U S A. 1994;91(25):12173–7.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  13. Raab G, Klagsbrun M. Heparin-binding EGF-like growth factor. Biochim Biophys Acta. 1997;1333(3):F179–99.

    CAS  PubMed  Google Scholar 

  14. Massague J, Pandiella A. Membrane-anchored growth factors. Annu Rev Biochem. 1993;62:515–41.

    Article  CAS  PubMed  Google Scholar 

  15. Goishi K, Higashiyama S, Klagsbrun M, Nakano N, Umata T, Ishikawa M, Mekada E, Taniguchi N. Phorbol ester induces the rapid processing of cell surface heparin-binding EGF-like growth factor: conversion from juxtacrine to paracrine growth factor activity. Mol Biol Cell. 1995;6(8):967–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Izumi Y, Hirata M, Hasuwa H, Iwamoto R, Umata T, Miyado K, Tamai Y, Kurisaki T, Sehara-Fujisawa A, Ohno S, Mekada E. A metalloprotease-disintegrin, MDC9/meltrin-gamma/ADAM9 and PKCdelta are involved in TPA-induced ectodomain shedding of membrane-anchored heparin-binding EGF-like growth factor. EMBO J. 1998;17(24):7260–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Raab G, Kover K, Paria BC, Dey SK, Ezzell RM, Klagsbrun M. Mouse preimplantation blastocysts adhere to cells expressing the transmembrane form of heparin-binding EGF-like growth factor. Development. 1996;122(2):637–45.

    Article  CAS  PubMed  Google Scholar 

  18. Nakamura K, Iwamoto R, Mekada E. Membrane-anchored heparin-binding EGF-like growth factor (HB-EGF) and diphtheria toxin receptor-associated protein (DRAP27)/CD9 form a complex with integrin alpha 3 beta 1 at cell-cell contact sites. J Cell Biol. 1995;129(6):1691–705.

    Article  CAS  PubMed  Google Scholar 

  19. Mekada E, Okada Y, Uchida T. Identification of diphtheria toxin receptor and a nonproteinous diphtheria toxin-binding molecule in Vero cell membrane. J Cell Biol. 1988;107(2):511–9.

    Article  CAS  PubMed  Google Scholar 

  20. Naglich JG, Metherall JE, Russell DW, Eidels L. Expression cloning of a diphtheria toxin receptor: identity with a heparin-binding EGF-like growth factor precursor. Cell. 1992;69(6):1051–61.

    Article  CAS  PubMed  Google Scholar 

  21. Higashiyama S, Iwamoto R, Goishi K, Raab G, Taniguchi N, Klagsbrun M, Mekada E. The membrane protein CD9/DRAP 27 potentiates the juxtacrine growth factor activity of the membrane-anchored heparin-binding EGF-like growth factor. J Cell Biol. 1995;128(5):929–38.

    Article  CAS  PubMed  Google Scholar 

  22. Iwamoto R, Senoh H, Okada Y, Uchida T, Mekada E. An antibody that inhibits the binding of diphtheria toxin to cells revealed the association of a 27-kDa membrane protein with the diphtheria toxin receptor. J Biol Chem. 1991;266(30):20463–9.

    Article  CAS  PubMed  Google Scholar 

  23. Iwamoto R, Higashiyama S, Mitamura T, Taniguchi N, Klagsbrun M, Mekada E. Heparin-binding EGF-like growth factor, which acts as the diphtheria toxin receptor, forms a complex with membrane protein DRAP27/CD9, which up-regulates functional receptors and diphtheria toxin sensitivity. EMBO J. 1994;13(10):2322–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lanzrein M, Garred O, Olsnes S, Sandvig K. Diphtheria toxin endocytosis and membrane translocation are dependent on the intact membrane-anchored receptor (HB-EGF precursor): studies on the cell-associated receptor cleaved by a metalloprotease in phorbol-ester-treated cells. Biochem J. 1995;310(Pt 1):285–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Diaz B, Yuen A, Iizuka S, Higashiyama S, Courtneidge SA. Notch increases the shedding of HB-EGF by ADAM12 to potentiate invadopodia formation in hypoxia. J Cell Biol. 2013;201(2):279–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Li P, Deng Q, Liu J, Yan J, Wei Z, Zhang Z, Liu H, Li B. Roles for HB-EGF in mesenchymal stromal cell proliferation and differentiation during skeletal growth. J Bone Miner Res. 2019;34(2):295–309.

    Article  CAS  PubMed  Google Scholar 

  27. Puschmann TB, Zanden C, Lebkuechner I, Philippot C, de Pablo Y, Liu J, Pekny M. HB-EGF affects astrocyte morphology, proliferation, differentiation, and the expression of intermediate filament proteins. J Neurochem. 2014;128(6):878–89.

    Article  CAS  PubMed  Google Scholar 

  28. Kim YS, Yuan J, Dewar A, Borg JP, Threadgill DW, Sun X, Dey SK. An unanticipated discourse of HB-EGF with VANGL2 signaling during embryo implantation. Proc Natl Acad Sci U S A. 2023;120(20):e2302937120.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Liu J, Gao F, Liu YF, Dou HT, Yan JQ, Fan ZM, Yang ZM. HB-EGF regulates Prss56 expression during mouse decidualization via EGFR/ERK/EGR2 signaling pathway. J Endocrinol. 2017;234(3):247–54.

    Article  CAS  PubMed  Google Scholar 

  30. Wang X, Wang H, Matsumoto H, Roy SK, Das SK, Paria BC. Dual source and target of heparin-binding EGF-like growth factor during the onset of implantation in the hamster. Development. 2002;129(17):4125–34.

    Article  CAS  PubMed  Google Scholar 

  31. Kim YJ, Lee GS, Hyun SH, Ka HH, Choi KC, Lee CK, Jeung EB. Uterine expression of epidermal growth factor family during the course of pregnancy in pigs. Reprod Domest Anim. 2009;44(5):797–804.

    Article  CAS  PubMed  Google Scholar 

  32. Kim GY, Besner GE, Steffen CL, McCarthy DW, Downing MT, Luquette MH, Abad MS, Brigstock DR. Purification of heparin-binding epidermal growth factor-like growth factor from pig uterine luminal flushings, and its production by endometrial tissues. Biol Reprod. 1995;52(3):561–71.

    Article  CAS  PubMed  Google Scholar 

  33. Kliem A, Tetens F, Klonisch T, Grealy M, Fischer B. Epidermal growth factor receptor and ligands in elongating bovine blastocysts. Mol Reprod Dev. 1998;51(4):402–12.

    Article  CAS  PubMed  Google Scholar 

  34. Takatsu K, Acosta TJ. Expression of heparin-binding EGF-like growth factor (HB-EGF) in bovine endometrium: effects of HB-EGF and interferon-tau on prostaglandin production. Reprod Domest Anim. 2015;50(3):458–64.

    Article  CAS  PubMed  Google Scholar 

  35. Lee DS, Yanagimoto Ueta Y, Xuan X, Igarashi I, Fujisaki K, Sugimoto C, Toyoda Y, Suzuki H. Expression patterns of the implantation-associated genes in the uterus during the estrous cycle in mice. J Reprod Dev. 2005;51(6):787–98.

    Article  CAS  PubMed  Google Scholar 

  36. Das SK, Wang XN, Paria BC, Damm D, Abraham JA, Klagsbrun M, Andrews GK, Dey SK. Heparin-binding EGF-like growth factor gene is induced in the mouse uterus temporally by the blastocyst solely at the site of its apposition: a possible ligand for interaction with blastocyst EGF-receptor in implantation. Development. 1994;120(5):1071–83.

    Article  CAS  PubMed  Google Scholar 

  37. Lessey BA, Gui Y, Apparao KB, Young SL, Mulholland J. Regulated expression of heparin-binding EGF-like growth factor (HB-EGF) in the human endometrium: a potential paracrine role during implantation. Mol Reprod Dev. 2002;62(4):446–55.

    Article  CAS  PubMed  Google Scholar 

  38. Yoo HJ, Barlow DH, Mardon HJ. Temporal and spatial regulation of expression of heparin-binding epidermal growth factor-like growth factor in the human endometrium: a possible role in blastocyst implantation. Dev Genet. 1997;21(1):102–8.

    Article  CAS  PubMed  Google Scholar 

  39. Leach RE, Khalifa R, Ramirez ND, Das SK, Wang J, Dey SK, Romero R, Armant DR. Multiple roles for heparin-binding epidermal growth factor-like growth factor are suggested by its cell-specific expression during the human endometrial cycle and early placentation. J Clin Endocrinol Metab. 1999;84(9):3355–63.

    CAS  PubMed  Google Scholar 

  40. Chobotova K, Muchmore ME, Carver J, Yoo HJ, Manek S, Gullick WJ, Barlow DH, Mardon HJ. The mitogenic potential of heparin-binding epidermal growth factor in the human endometrium is mediated by the epidermal growth factor receptor and is modulated by tumor necrosis factor-alpha. J Clin Endocrinol Metab. 2002;87(12):5769–77.

    Article  CAS  PubMed  Google Scholar 

  41. Birdsall MA, Hopkisson JF, Grant KE, Barlow DH, Mardon HJ. Expression of heparin-binding epidermal growth factor messenger RNA in the human endometrium. Mol Hum Reprod. 1996;2(1):31–4.

    Article  CAS  PubMed  Google Scholar 

  42. Wang H, Dey SK. Lipid signaling in embryo implantation. Prostaglandins Other Lipid Mediat. 2005;77(1-4):84–102.

    Article  CAS  PubMed  Google Scholar 

  43. Deryabin PI, Borodkina AV. Stromal cell senescence contributes to impaired endometrial decidualization and defective interaction with trophoblast cells. Hum Reprod. 2022;37(7):1505–24.

    Article  CAS  PubMed  Google Scholar 

  44. Wang XN, Das SK, Damm D, Klagsbrun M, Abraham JA, Dey SK. Differential regulation of heparin-binding epidermal growth factor-like growth factor in the adult ovariectomized mouse uterus by progesterone and estrogen. Endocrinology. 1994;135(3):1264–71.

    Article  CAS  PubMed  Google Scholar 

  45. Zhang Z, Funk C, Roy D, Glasser S, Mulholland J. Heparin-binding epidermal growth factor-like growth factor is differentially regulated by progesterone and estradiol in rat uterine epithelial and stromal cells. Endocrinology. 1994;134(3):1089–94.

    Article  CAS  PubMed  Google Scholar 

  46. Paria BC, Huet-Hudson YM, Dey SK. Blastocyst’s state of activity determines the “window” of implantation in the receptive mouse uterus. Proc Natl Acad Sci U S A. 1993;90(21):10159–62.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  47. Castro-Rendon WA, Castro-Alvarez JF, Guzman-Martinez C, Bueno-Sanchez JC. Blastocyst-endometrium interaction: intertwining a cytokine network. Braz J Med Biol Res. 2006;39(11):1373–85.

    Article  CAS  PubMed  Google Scholar 

  48. Armant DR, Wang J, Liu Z. Intracellular signaling in the developing blastocyst as a consequence of the maternal-embryonic dialogue. Semin Reprod Med. 2000;18(3):273–87.

    Article  CAS  PubMed  Google Scholar 

  49. Mishra A, Seshagiri PB. Heparin binding-epidermal growth factor improves blastocyst hatching and trophoblast outgrowth in the golden hamster. Reprod Biomed Online. 2000;1(3):87–95.

    Article  CAS  PubMed  Google Scholar 

  50. Tan Y, Li M, Cox S, Davis MK, Tawfik O, Paria BC, Das SK. HB-EGF directs stromal cell polyploidy and decidualization via cyclin D3 during implantation. Dev Biol. 2004;265(1):181–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Tan J, Raja S, Davis MK, Tawfik O, Dey SK, Das SK. Evidence for coordinated interaction of cyclin D3 with p21 and cdk6 in directing the development of uterine stromal cell decidualization and polyploidy during implantation. Mech Dev. 2002;111(1-2):99–113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Afzal J, Du W, Novin A, Liu Y, Wali K, Murthy A, Garen A, Wagner G. Kshitiz, Paracrine HB-EGF signaling reduce enhanced contractile and energetic state of activated decidual fibroblasts by rebalancing SRF-MRTF-TCF transcriptional axis, Front Cell. Dev Biol. 2022;10:927631.

    Google Scholar 

  53. Umezu-Goto M, Kishi Y, Taira A, Hama K, Dohmae N, Takio K, Yamori T, Mills GB, Inoue K, Aoki J, Arai H. Autotaxin has lysophospholipase D activity leading to tumor cell growth and motility by lysophosphatidic acid production. J Cell Biol. 2002;158(2):227–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Aikawa S, Hashimoto T, Kano K, Aoki J. Lysophosphatidic acid as a lipid mediator with multiple biological actions. J Biochem. 2015;157(2):81–9.

    Article  CAS  PubMed  Google Scholar 

  55. Aikawa S, Kano K, Inoue A, Wang J, Saigusa D, Nagamatsu T, Hirota Y, Fujii T, Tsuchiya S, Taketomi Y, Sugimoto Y, Murakami M, Arita M, Kurano M, Ikeda H, Yatomi Y, Chun J, Aoki J. Autotaxin-lysophosphatidic acid-LPA(3) signaling at the embryo-epithelial boundary controls decidualization pathways. EMBO J. 2017;36(14):2146–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Liu Z, Armant DR. Lysophosphatidic acid regulates murine blastocyst development by transactivation of receptors for heparin-binding EGF-like growth factor. Exp Cell Res. 2004;296(2):317–26.

    Article  CAS  PubMed  Google Scholar 

  57. Li Y, Chen ST, He YY, Li B, Yang C, Yang ZS, Yang ZM. The regulation and function of acetylated high-mobility group box 1 during implantation and decidualization. Front Immunol. 2023;14:1024706.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Tamada H, Higashiyama C, Takano H, Kawate N, Inaba T, Sawada T. The effects of heparin-binding epidermal growth factor-like growth factor on preimplantation-embryo development and implantation in the rat. Life Sci. 1999;64(22):1967–73.

    Article  CAS  PubMed  Google Scholar 

  59. Gonzalez M, Neufeld J, Reimann K, Wittmann S, Samalecos A, Wolf A, Bamberger AM, Gellersen B. Expansion of human trophoblastic spheroids is promoted by decidualized endometrial stromal cells and enhanced by heparin-binding epidermal growth factor-like growth factor and interleukin-1 beta. Mol Hum Reprod. 2011;17(7):421–33.

    Article  CAS  PubMed  Google Scholar 

  60. Fang CX, Nong YQ, Liu FH, Fan L, Chen Y. Heparin-binding epidermal growth factor-like growth factor enhances aquaporin 3 expression and function during mouse embryo implantation. Reprod Sci. 2017;24(3):463–70.

    Article  CAS  PubMed  Google Scholar 

  61. Moghani-Ghoroghi F, Moshkdanian G, Sehat M, Nematollahi-Mahani SN, Ragerdi-Kashani I, Pasbakhsh P. Melatonin pretreated blastocysts along with calcitonin administration improved implantation by upregulation of heparin binding-epidermal growth factor expression in murine endometrium. Cell J. 2018;19(4):599–606.

    PubMed  Google Scholar 

  62. He C, Wang J, Li Y, Zhu K, Xu Z, Song Y, Song Y, Liu G. Melatonin-related genes expressed in the mouse uterus during early gestation promote embryo implantation. J Pineal Res. 2015;58(3):300–9.

    Article  CAS  PubMed  Google Scholar 

  63. Stratmann HG, Mark AL, Williams GA. Thallium-201 perfusion imaging with atrial pacing or dipyridamole stress testing for evaluation of cardiac risk prior to nonvascular surgery. Clin Cardiol. 1990;13(9):611–6.

    Article  CAS  PubMed  Google Scholar 

  64. Hesam Shariati MB, Seghinsara AM, Shokrzadeh N, Niknafs B. The effect of fludrocortisone on the uterine receptivity partially mediated by ERK1/2-mTOR pathway. J Cell Physiol. 2019;234(11):20098–110.

    Article  CAS  PubMed  Google Scholar 

  65. Paria BC, Ma W, Tan J, Raja S, Das SK, Dey SK, Hogan BL. Cellular and molecular responses of the uterus to embryo implantation can be elicited by locally applied growth factors. Proc Natl Acad Sci U S A. 2001;98(3):1047–52.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  66. Yue L, Yu HF, Yang ZQ, Tian XC, Zheng LW, Guo B. Egr2 mediates the differentiation of mouse uterine stromal cells responsiveness to HB-EGF during decidualization. J Exp Zool B Mol Dev Evol. 2018;330(4):215–24.

    Article  CAS  PubMed  Google Scholar 

  67. Yu HF, Duan CC, Yang ZQ, Wang YS, Yue ZP, Guo B. HB-EGF ameliorates oxidative stress-mediated uterine decidualization damage. Oxid Med Cell Longev. 2019;2019:6170936.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Hong JH, Hwang ES, McManus MT, Amsterdam A, Tian Y, Kalmukova R, Mueller E, Benjamin T, Spiegelman BM, Sharp PA, Hopkins N, Yaffe MB. TAZ, a transcriptional modulator of mesenchymal stem cell differentiation. Science. 2005;309(5737):1074–8.

    Article  ADS  CAS  PubMed  Google Scholar 

  69. Yu FX, Zhao B, Guan KL. Hippo pathway in organ size control, tissue homeostasis, and cancer. Cell. 2015;163(4):811–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Yu HF, Zheng LW, Yang ZQ, Wang YS, Wang TT, Yue ZP, Guo B. TAZ as a novel regulator of oxidative damage in decidualization via Nrf2/ARE/Foxo1 pathway. Exp Mol Med. 2021;53(9):1307–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Jin ZY, Liu CK, Hong YQ, Liang YX, Liu L, Yang ZM. BHPF exposure impairs mouse and human decidualization. Environ Pollut. 2022;304:119222.

    Article  CAS  PubMed  Google Scholar 

  72. Zhang XH, Liang X, Wang TS, Liang XH, Zuo RJ, Deng WB, Zhang ZR, Qin FN, Zhao ZA, Yang ZM. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) induction on Snail expression during mouse decidualization. Mol Cell Endocrinol. 2013;381(1-2):272–9.

    Article  CAS  PubMed  Google Scholar 

  73. Qi QR, Zhao XY, Zuo RJ, Wang TS, Gu XW, Liu JL, Yang ZM. Involvement of atypical transcription factor E2F8 in the polyploidization during mouse and human decidualization. Cell Cycle. 2015;14(12):1842–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Yu HF, Duan CC, Yang ZQ, Wang YS, Yue ZP, Guo B. Malic enzyme 1 is important for uterine decidualization in response to progesterone/cAMP/PKA/HB-EGF pathway. FASEB J. 2020;34(3):3820–37.

    Article  CAS  PubMed  Google Scholar 

  75. Wang Y, Li J, Ying Wang C, Yan Kwok AH, Leung FC. Epidermal growth factor (EGF) receptor ligands in the chicken ovary: I. Evidence for heparin-binding EGF-like growth factor (HB-EGF) as a potential oocyte-derived signal to control granulosa cell proliferation and HB-EGF and kit ligand expression. Endocrinology. 2007;148(7):3426–40.

    Article  CAS  PubMed  Google Scholar 

  76. Pan B, Sengoku K, Takuma N, Goishi K, Horikawa M, Tamate K, Ishikawa M. Differential expression of heparin-binding epidermal growth factor-like growth factor in the rat ovary. Mol Cell Endocrinol. 2004;214(1-2):1–8.

    Article  CAS  PubMed  Google Scholar 

  77. Akayama Y, Takekida S, Ohara N, Tateiwa H, Chen W, Nakabayashi K, Maruo T. Gene expression and immunolocalization of heparin-binding epidermal growth factor-like growth factor and human epidermal growth factor receptors in human corpus luteum. Hum Reprod. 2005;20(10):2708–14.

    Article  CAS  PubMed  Google Scholar 

  78. Cecconi S, Ciccarelli C, Barberi M, Macchiarelli G, Canipari R. Granulosa cell-oocyte interactions. Eur J Obstet Gynecol Reprod Biol. 2004;115(Suppl 1):S19–22.

    Article  PubMed  Google Scholar 

  79. Canipari R. Oocyte--granulosa cell interactions. Hum Reprod Update. 2000;6(3):279–89.

    Article  CAS  PubMed  Google Scholar 

  80. Pan B, Sengoku K, Goishi K, Takuma N, Yamashita T, Wada K, Ishikawa M. The soluble and membrane-anchored forms of heparin-binding epidermal growth factor-like growth factor appear to play opposing roles in the survival and apoptosis of human luteinized granulosa cells. Mol Hum Reprod. 2002;8(8):734–41.

    Article  CAS  PubMed  Google Scholar 

  81. Karakida S, Kawano Y, Utsunomiya Y, Furukawa Y, Sasaki T, Narahara H. Effect of heparin-binding EGF-like growth factor and amphiregulin on the MAP kinase-induced production of vascular endothelial growth factor by human granulosa cells. Growth Factors. 2011;29(6):271–7.

    Article  CAS  PubMed  Google Scholar 

  82. Clark BJ, Wells J, King SR, Stocco DM. The purification, cloning, and expression of a novel luteinizing hormone-induced mitochondrial protein in MA-10 mouse Leydig tumor cells. Characterization of the steroidogenic acute regulatory protein (StAR). J Biol Chem. 1994;269(45):28314–22.

    Article  CAS  PubMed  Google Scholar 

  83. Stocco DM, Clark BJ. Regulation of the acute production of steroids in steroidogenic cells. Endocr Rev. 1996;17(3):221–44.

    CAS  PubMed  Google Scholar 

  84. Cheng JC, Han X, Meng Q, Guo Y, Liu B, Song T, Jia Y, Fang L, Sun YP. HB-EGF upregulates StAR expression and stimulates progesterone production through ERK1/2 signaling in human granulosa-lutein cells. Cell Commun Signal. 2022;20(1):166.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Wang T, Liu Y, Lv M, Xing Q, Zhang Z, He X, Xu Y, Wei Z, Cao Y. miR-323-3p regulates the steroidogenesis and cell apoptosis in polycystic ovary syndrome (PCOS) by targeting IGF-1. Gene. 2019;683:87–100.

    Article  CAS  PubMed  Google Scholar 

  86. Wang F, Pan J, Liu Y, Meng Q, Lv P, Qu F, Ding GL, Klausen C, Leung PC, Chan HC, Yao W, Zhou CY, Shi B, Zhang J, Sheng J, Huang H. Alternative splicing of the androgen receptor in polycystic ovary syndrome. Proc Natl Acad Sci U S A. 2015;112(15):4743–8.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  87. Coffler MS, Patel K, Dahan MH, Yoo RY, Malcom PJ, Chang RJ. Enhanced granulosa cell responsiveness to follicle-stimulating hormone during insulin infusion in women with polycystic ovary syndrome treated with pioglitazone. J Clin Endocrinol Metab. 2003;88(12):5624–31.

    Article  CAS  PubMed  Google Scholar 

  88. Franks S, Mason H, Willis D. Follicular dynamics in the polycystic ovary syndrome. Mol Cell Endocrinol. 2000;163(1-2):49–52.

    Article  CAS  PubMed  Google Scholar 

  89. Huang JC, Duan CC, Jin S, Sheng CB, Wang YS, Yue ZP, Guo B. HB-EGF induces mitochondrial dysfunction via estrogen hypersecretion in granulosa cells dependent on cAMP-PKA-JNK/ERK-Ca(2+)-FOXO1 pathway. Int J Biol Sci. 2022;18(5):2047–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Wu YX, Lin YS, Li SC, Yao X, Cheng M, Zhu L, Liu HY. microRNA-194 is increased in polycystic ovary syndrome granulosa cell and induce KGN cells apoptosis by direct targeting heparin-binding EGF-like growth factor. Reprod Biol Endocrinol. 2021;19(1):170.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Frey MK, Pothuri B. Homologous recombination deficiency (HRD) testing in ovarian cancer clinical practice: a review of the literature. Gynecol Oncol Res Pract. 2017;4:4.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Tan DS, Agarwal R, Kaye SB. Mechanisms of transcoelomic metastasis in ovarian cancer. Lancet Oncol. 2006;7(11):925–34.

    Article  PubMed  Google Scholar 

  93. Thibault B, Castells M, Delord JP, Couderc B. Ovarian cancer microenvironment: implications for cancer dissemination and chemoresistance acquisition. Cancer Metastasis Rev. 2014;33(1):17–39.

    Article  CAS  PubMed  Google Scholar 

  94. Crawford SC, Vasey PA, Paul J, Hay A, Davis JA, Kaye SB. Does aggressive surgery only benefit patients with less advanced ovarian cancer? Results from an international comparison within the SCOTROC-1 Trial. J Clin Oncol. 2005;23(34):8802–11.

    Article  PubMed  Google Scholar 

  95. Trimble EL, Wright J, Christian MC. Treatment of platinum-resistant ovarian cancer. Expert Opin Pharmacother. 2001;2(8):1299–306.

    Article  CAS  PubMed  Google Scholar 

  96. Oza AM, Cook AD, Pfisterer J, Embleton A, Ledermann JA, Pujade-Lauraine E, Kristensen G, Carey MS, Beale P, Cervantes A, Park-Simon TW, Rustin G, Joly F, Mirza MR, Plante M, Quinn M, Poveda A, Jayson GC, Stark D, et al. Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial. Lancet Oncol. 2015;16(8):928–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Yotsumoto F, Yagi H, Suzuki SO, Oki E, Tsujioka H, Hachisuga T, Sonoda K, Kawarabayashi T, Mekada E, Miyamoto S. Validation of HB-EGF and amphiregulin as targets for human cancer therapy. Biochem Biophys Res Commun. 2008;365(3):555–61.

    Article  CAS  PubMed  Google Scholar 

  98. Miyamoto S, Hirata M, Yamazaki A, Kageyama T, Hasuwa H, Mizushima H, Tanaka Y, Yagi H, Sonoda K, Kai M, Kanoh H, Nakano H, Mekada E. Heparin-binding EGF-like growth factor is a promising target for ovarian cancer therapy. Cancer Res. 2004;64(16):5720–7.

    Article  CAS  PubMed  Google Scholar 

  99. Yagi H, Miyamoto S, Tanaka Y, Sonoda K, Kobayashi H, Kishikawa T, Iwamoto R, Mekada E, Nakano H. Clinical significance of heparin-binding epidermal growth factor-like growth factor in peritoneal fluid of ovarian cancer. Br J Cancer. 2005;92(9):1737–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Tanaka Y, Miyamoto S, Suzuki SO, Oki E, Yagi H, Sonoda K, Yamazaki A, Mizushima H, Maehara Y, Mekada E, Nakano H. Clinical significance of heparin-binding epidermal growth factor-like growth factor and a disintegrin and metalloprotease 17 expression in human ovarian cancer. Clin Cancer Res. 2005;11(13):4783–92.

    Article  CAS  PubMed  Google Scholar 

  101. Rogmans C, Feuerborn J, Treeck L, Tribian N, Flörkemeier I, Arnold N, Weimer JP, Maass N, Jansen P, Lieb W, Dempfle A, Bauerschlag DO, Hedemann N. Nectin-4 as blood-based biomarker enables detection of early ovarian cancer stages. Cancers (Basel). 2022;14(23):5867. https://doi.org/10.3390/cancers14235867.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Miyata K, Yotsumoto F, Fukagawa S, Kiyoshima C, Ouk NS, Urushiyama D, Ito T, Katsuda T, Kurakazu M, Araki R, Sanui A, Miyahara D, Murata M, Shirota K, Yagi H, Takono T, Kato K, Yaegashi N, Akazawa K, et al. Serum heparin-binding epidermal growth factor-like growth factor (HB-EGF) as a biomarker for primary ovarian cancer. Anticancer Res. 2017;37(7):3955–60.

    PubMed  Google Scholar 

  103. Izuchi D, Fukagawa S, Yotsumoto F, Shigekawa K, Yoshikawa K, Hirakawa T, Kiyoshima C, Ouk NS, Urushiyama D, Katsuda T, Miyata K, Ito T, Kurakazu M, Araki R, Sanui A, Miyahara D, Murata M, Ito H, Shirota K, et al. Association of serum HB-EGF value and response to chemotherapy in patients with recurrent ovarian cancer. Anticancer Res. 2018;38(7):4347–51.

    Article  CAS  PubMed  Google Scholar 

  104. Hikita S, Yotsumoto F, Fukami T, Horiuchi S, Sanui A, Miyata K, Nam SO, Tsujioka H, Ueda T, Shirota K, Yoshizato T, Maeda K, Ishikawa T, Okuno Y, Kuroki M, Mekada E, Miyamoto S. Assessment of HB-EGF levels in peritoneal fluid and serum of ovarian cancer patients using ELISA. Anticancer Res. 2011;31(7):2553–9.

    CAS  PubMed  Google Scholar 

  105. Yamazaki S, Iwamoto R, Saeki K, Asakura M, Takashima S, Yamazaki A, Kimura R, Mizushima H, Moribe H, Higashiyama S, Endoh M, Kaneda Y, Takagi S, Itami S, Takeda N, Yamada G, Mekada E. Mice with defects in HB-EGF ectodomain shedding show severe developmental abnormalities. J Cell Biol. 2003;163(3):469–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Yu Y, Zhang M, Zhang X, Cai Q, Zhu Z, Jiang W, Xu C. Transactivation of epidermal growth factor receptor through platelet-activating factor/receptor in ovarian cancer cells. J Exp Clin Cancer Res. 2014;33(1):85.

    Article  PubMed  PubMed Central  Google Scholar 

  107. Koshikawa N, Mizushima H, Minegishi T, Eguchi F, Yotsumoto F, Nabeshima K, Miyamoto S, Mekada E, Seiki M. Proteolytic activation of heparin-binding EGF-like growth factor by membrane-type matrix metalloproteinase-1 in ovarian carcinoma cells. Cancer Sci. 2011;102(1):111–6.

    Article  CAS  PubMed  Google Scholar 

  108. Bolitho C, Hahn MA, Baxter RC, Marsh DJ. The chemokine CXCL1 induces proliferation in epithelial ovarian cancer cells by transactivation of the epidermal growth factor receptor. Endocr Relat Cancer. 2010;17(4):929–40.

    Article  CAS  PubMed  Google Scholar 

  109. Nowak M, Klink M. The role of tumor-associated macrophages in the progression and chemoresistance of ovarian cancer. Cells. 2020;9(5):1299. https://doi.org/10.3390/cells9051299.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Song M, Yeku OO, Rafiq S, Purdon T, Dong X, Zhu L, Zhang T, Wang H, Yu Z, Mai J, Shen H, Nixon B, Li M, Brentjens RJ, Ma X. Tumor derived UBR5 promotes ovarian cancer growth and metastasis through inducing immunosuppressive macrophages. Nat Commun. 2020;11(1):6298.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  111. Carroll MJ, Kapur A, Felder M, Patankar MS, Kreeger PK. M2 macrophages induce ovarian cancer cell proliferation via a heparin binding epidermal growth factor/matrix metalloproteinase 9 intercellular feedback loop. Oncotarget. 2016;7(52):86608–20.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Yagi H, Yotsumoto F, Miyamoto S. Heparin-binding epidermal growth factor-like growth factor promotes transcoelomic metastasis in ovarian cancer through epithelial-mesenchymal transition. Mol Cancer Ther. 2008;7(10):3441–51.

    Article  CAS  PubMed  Google Scholar 

  113. Hausen HZ. Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer. 2002;2(5):342–50.

    Article  PubMed  Google Scholar 

  114. Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV, Snijders PJ, Peto J, Meijer CJ, Munoz N. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 1999;189(1):12–9.

    Article  CAS  PubMed  Google Scholar 

  115. de Martel C, Ferlay J, Franceschi S, Vignat J, Bray F, Forman D, Plummer M. Global burden of cancers attributable to infections in 2008: a review and synthetic analysis. Lancet Oncol. 2012;13(6):607–15.

    Article  PubMed  Google Scholar 

  116. Joura EA, Ault KA, Bosch FX, Brown D, Cuzick J, Ferris D, Garland SM, Giuliano AR, Hernandez-Avila M, Huh W, Iversen OE, Kjaer SK, Luna J, Miller D, Monsonego J, Munoz N, Myers E, Paavonen J, Pitisuttithum P, et al. Attribution of 12 high-risk human papillomavirus genotypes to infection and cervical disease. Cancer Epidemiol Biomarkers Prev. 2014;23(10):1997–2008.

    Article  PubMed  Google Scholar 

  117. Bhowmick NA, Neilson EG, Moses HL. Stromal fibroblasts in cancer initiation and progression. Nature. 2004;432(7015):332–7.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  118. Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer. 2006;6(5):392–401.

    Article  CAS  PubMed  Google Scholar 

  119. Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, Carey VJ, Richardson AL, Weinberg RA. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 2005;121(3):335–48.

    Article  CAS  PubMed  Google Scholar 

  120. Fujimoto J, Sakaguchi H, Aoki I, Tamaya T. Clinical implications of expression of interleukin 8 related to angiogenesis in uterine cervical cancers. Cancer Res. 2000;60(10):2632–5.

    CAS  PubMed  Google Scholar 

  121. Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer. 2004;4(1):71–8.

    Article  CAS  PubMed  Google Scholar 

  122. Murata T, Mizushima H, Chinen I, Moribe H, Yagi S, Hoffman RM, Kimura T, Yoshino K, Ueda Y, Enomoto T, Mekada E. HB-EGF and PDGF mediate reciprocal interactions of carcinoma cells with cancer-associated fibroblasts to support progression of uterine cervical cancers. Cancer Res. 2011;71(21):6633–42.

    Article  CAS  PubMed  Google Scholar 

  123. Schrevel M, Osse EM, Prins FA, Trimbos J, Fleuren GJ, Gorter A, Jordanova ES. Autocrine expression of the epidermal growth factor receptor ligand heparin-binding EGF-like growth factor in cervical cancer. Int J Oncol. 2017;50(6):1947–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49.

    Article  PubMed  Google Scholar 

  125. Haffty BG, Yang Q, Reiss M, Kearney T, Higgins SA, Weidhaas J, Harris L, Hait W, Toppmeyer D. Locoregional relapse and distant metastasis in conservatively managed triple negative early-stage breast cancer. J Clin Oncol. 2006;24(36):5652–7.

    Article  PubMed  Google Scholar 

  126. Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA, Lickley LA, Rawlinson E, Sun P, Narod SA. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res. 2007;13(15 Pt 1):4429–34.

    Article  PubMed  Google Scholar 

  127. Couzin J. Cancer research. Probing the roots of race and cancer. Science. 2007;315(5812):592–4.

    Article  CAS  PubMed  Google Scholar 

  128. Normanno N, De Luca A, Maiello MR, Campiglio M, Napolitano M, Mancino M, Carotenuto A, Viglietto G, Menard S. The MEK/MAPK pathway is involved in the resistance of breast cancer cells to the EGFR tyrosine kinase inhibitor gefitinib. J Cell Physiol. 2006;207(2):420–7.

    Article  CAS  PubMed  Google Scholar 

  129. Revillion F, Lhotellier V, Hornez L, Bonneterre J, Peyrat JP. ErbB/HER ligands in human breast cancer, and relationships with their receptors, the bio-pathological features and prognosis. Ann Oncol. 2008;19(1):73–80.

    Article  CAS  PubMed  Google Scholar 

  130. Olsen DA, Bechmann T, Ostergaard B, Wamberg PA, Jakobsen EH, Brandslund I. Increased concentrations of growth factors and activation of the EGFR system in breast cancer. Clin Chem Lab Med. 2012;50(10):1809–18.

    Article  CAS  PubMed  Google Scholar 

  131. David M, Sahay D, Mege F, Descotes F, Leblanc R, Ribeiro J, Clezardin P, Peyruchaud O. Identification of heparin-binding EGF-like growth factor (HB-EGF) as a biomarker for lysophosphatidic acid receptor type 1 (LPA1) activation in human breast and prostate cancers. PLoS One. 2014;9(5):e97771.

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  132. Gyorffy B, Lanczky A, Eklund AC, Denkert C, Budczies J, Li Q, Szallasi Z. An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients. Breast Cancer Res Treat. 2010;123(3):725–31.

    Article  PubMed  Google Scholar 

  133. Shetty P, Patil VS, Mohan R, D’souza LC, Bargale A, Patil BR, Dinesh US, Haridas V, Kulkarni SP. Annexin A2 and its downstream IL-6 and HB-EGF as secretory biomarkers in the differential diagnosis of Her-2 negative breast cancer. Ann Clin Biochem. 2017;54(4):463–71.

    Article  CAS  PubMed  Google Scholar 

  134. Ito Y, Takeda T, Higashiyama S, Noguchi S, Matsuura N. Expression of heparin-binding epidermal growth factor-like growth factor in breast carcinoma. Breast Cancer Res Treat. 2001;67(1):81–5.

    Article  CAS  PubMed  Google Scholar 

  135. Kjaer IM, Olsen DA, Brandslund I, Bechmann T, Jakobsen EH, Bogh SB, Madsen JS. Prognostic impact of serum levels of EGFR and EGFR ligands in early-stage breast cancer. Sci Rep. 2020;10(1):16558.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  136. Harris AL. Hypoxia--a key regulatory factor in tumour growth. Nat Rev Cancer. 2002;2(1):38–47.

    Article  CAS  PubMed  Google Scholar 

  137. Semenza GL. The hypoxic tumor microenvironment: a driving force for breast cancer progression. Biochim Biophys Acta. 2016;1863(3):382–91.

    Article  CAS  PubMed  Google Scholar 

  138. Araos J, Sleeman JP, Garvalov BK. The role of hypoxic signalling in metastasis: towards translating knowledge of basic biology into novel anti-tumour strategies. Clin Exp Metastasis. 2018;35(7):563–99.

    Article  CAS  PubMed  Google Scholar 

  139. Wang R, Godet I, Yang Y, Salman S, Lu H, Lyu Y, Zuo Q, Wang Y, Zhu Y, Chen C, He J, Gilkes DM, Semenza GL. Hypoxia-inducible factor-dependent ADAM12 expression mediates breast cancer invasion and metastasis. Proc Natl Acad Sci USA. 2021;118(19):e2020490118. https://doi.org/10.1073/pnas.2020490118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Yotsumoto F, Tokunaga E, Oki E, Maehara Y, Yamada H, Nakajima K, Nam SO, Miyata K, Koyanagi M, Doi K, Shirasawa S, Kuroki M, Miyamoto S. Molecular hierarchy of heparin-binding EGF-like growth factor-regulated angiogenesis in triple-negative breast cancer. Mol Cancer Res. 2013;11(5):506–17.

    Article  CAS  PubMed  Google Scholar 

  141. Sethuraman A, Brown M, Krutilina R, Wu ZH, Seagroves TN, Pfeffer LM, Fan M. BHLHE40 confers a pro-survival and pro-metastatic phenotype to breast cancer cells by modulating HBEGF secretion. Breast Cancer Res. 2018;20(1):117.

    Article  PubMed  PubMed Central  Google Scholar 

  142. Song P, Li Y, Dong Y, Liang Y, Qu H, Qi D, Lu Y, Jin X, Guo Y, Jia Y, Wang X, Xu W, Quan C. Estrogen receptor beta inhibits breast cancer cells migration and invasion through CLDN6-mediated autophagy. J Exp Clin Cancer Res. 2019;38(1):354.

    Article  PubMed  PubMed Central  Google Scholar 

  143. Razandi M, Pedram A, Park ST, Levin ER. Proximal events in signaling by plasma membrane estrogen receptors. J Biol Chem. 2003;278(4):2701–12.

    Article  CAS  PubMed  Google Scholar 

  144. Filardo EJ, Quinn JA, Bland KI, Frackelton AR Jr. Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF. Mol Endocrinol. 2000;14(10):1649–60.

    Article  CAS  PubMed  Google Scholar 

  145. Song RX, Zhang Z, Chen Y, Bao Y, Santen RJ. Estrogen signaling via a linear pathway involving insulin-like growth factor I receptor, matrix metalloproteinases, and epidermal growth factor receptor to activate mitogen-activated protein kinase in MCF-7 breast cancer cells. Endocrinology. 2007;148(8):4091–101.

    Article  CAS  PubMed  Google Scholar 

  146. Yonemitsu K, Miyasato Y, Shiota T, Shinchi Y, Fujiwara Y, Hosaka S, Yamamoto Y, Komohara Y. Soluble factors involved in cancer cell-macrophage interaction promote breast cancer growth. Anticancer Res. 2021;41(9):4249–58.

    Article  CAS  PubMed  Google Scholar 

  147. Vlaicu P, Mertins P, Mayr T, Widschwendter P, Ataseven B, Hogel B, Eiermann W, Knyazev P, Ullrich A. Monocytes/macrophages support mammary tumor invasivity by co-secreting lineage-specific EGFR ligands and a STAT3 activator. BMC Cancer. 2013;13:197.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Gu B, Shang X, Yan M, Li X, Wang W, Wang Q, Zhang C. Variations in incidence and mortality rates of endometrial cancer at the global, regional, and national levels, 1990-2019. Gynecol Oncol. 2021;161(2):573–80.

    Article  PubMed  Google Scholar 

  149. Onstad MA, Schmandt RE, Lu KH. Addressing the role of obesity in endometrial cancer risk, prevention, and treatment. J Clin Oncol. 2016;34(35):4225–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Young SL, Lessey BA, Fritz MA, Meyer WR, Murray MJ, Speckman PL, Nowicki BJ. In vivo and in vitro evidence suggest that HB-EGF regulates endometrial expression of human decay-accelerating factor. J Clin Endocrinol Metab. 2002;87(3):1368–75.

    Article  CAS  PubMed  Google Scholar 

  151. Hoffmann R, Sarkar Bhattacharya S, Roy D, Winterhoff B, Schmidmaier R, Dredge K, Hammond E, Shridhar V. Sulfated glycolipid PG545 induces endoplasmic reticulum stress and augments autophagic flux by enhancing anticancer chemotherapy efficacy in endometrial cancer. Biochem Pharmacol. 2020;178:114003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Ejskjaer K, Sorensen BS, Poulsen SS, Forman A, Nexo E, Mogensen O. Expression of the epidermal growth factor system in endometrioid endometrial cancer. Gynecol Oncol. 2007;104(1):158–67.

    Article  CAS  PubMed  Google Scholar 

  153. Dixit G, Pappas BA, Bhardwaj G, Schanz W, Maretzky T. Functional distinctions of endometrial cancer-associated mutations in the fibroblast growth factor receptor 2 gene. Cells. 2023;12(18):2227. https://doi.org/10.3390/cells12182227.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Mitamura T, Higashiyama S, Taniguchi N, Klagsbrun M, Mekada E. Diphtheria toxin binds to the epidermal growth factor (EGF)-like domain of human heparin-binding EGF-like growth factor/diphtheria toxin receptor and inhibits specifically its mitogenic activity. J Biol Chem. 1995;270(3):1015–9.

    Article  CAS  PubMed  Google Scholar 

  155. Kageyama T, Ohishi M, Miyamoto S, Mizushima H, Iwamoto R, Mekada E. Diphtheria toxin mutant CRM197 possesses weak EF2-ADP-ribosyl activity that potentiates its anti-tumorigenic activity. J Biochem. 2007;142(1):95–104.

    Article  CAS  PubMed  Google Scholar 

  156. Hamaoka M, Chinen I, Murata T, Takashima S, Iwamoto R, Mekada E. Anti-human HB-EGF monoclonal antibodies inhibiting ectodomain shedding of HB-EGF and diphtheria toxin binding. J Biochem. 2010;148(1):55–69.

    Article  CAS  PubMed  Google Scholar 

  157. Nam SO, Yotsumoto F, Miyata K, Suzaki Y, Yagi H, Odawara T, Manabe S, Ishikawa T, Kuroki M, Mekada E, Miyamoto S. Pre-clinical study of BK-UM, a novel inhibitor of HB-EGF, for ovarian cancer therapy. Anticancer Res. 2014;34(8):4615–20.

    CAS  PubMed  Google Scholar 

  158. Fukagawa S, Yotsumoto F, Odawara T, Manabe S, Ishikawa T, Yasunaga S, Miyamoto S. Antitumour effects of intravenous administration of BK-UM, a novel inhibitor of HB-EGF, in ovarian cancer therapy. Anticancer Res. 2017;37(7):3891–6.

    CAS  PubMed  Google Scholar 

  159. Miyamoto S, Yotsumoto F, Ueda T, Fukami T, Sanui A, Miyata K, Nam SO, Fukagawa S, Katsuta T, Maehara M, Kondo H, Miyahara D, Shirota K, Yoshizato T, Kuroki M, Nishikawa H, Saku K, Tsuboi Y, Ishitsuka K, et al. BK-UM in patients with recurrent ovarian cancer or peritoneal cancer: a first-in-human phase-I study. BMC Cancer. 2017;17(1):89.

    Article  PubMed  PubMed Central  Google Scholar 

  160. Tsujioka H, Fukami T, Yotsumoto F, Ueda T, Hikita S, Takahashi Y, Kondo H, Kuroki M, Miyamoto S. A possible clinical adaptation of CRM197 in combination with conventional chemotherapeutic agents for ovarian cancer. Anticancer Res. 2011;31(7):2461–5.

    CAS  PubMed  Google Scholar 

  161. Winterhoff B, Freyer L, Hammond E, Giri S, Mondal S, Roy D, Teoman A, Mullany SA, Hoffmann R, von Bismarck A, Chien J, Block MS, Millward M, Bampton D, Dredge K, Shridhar V. PG545 enhances anti-cancer activity of chemotherapy in ovarian models and increases surrogate biomarkers such as VEGF in preclinical and clinical plasma samples. Eur J Cancer. 2015;51(7):879–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Tang XH, Li M, Deng S, Lu MS. Cross-reacting material 197, a heparin-binding EGF-like growth factor inhibitor, reverses the chemoresistance in human cisplatin-resistant ovarian cancer. Anticancer Drugs. 2014;25(10):1201–10.

    Article  CAS  PubMed  Google Scholar 

  163. Tang XH, Deng S, Li M, Lu MS. The anti-tumor effect of cross-reacting material 197, an inhibitor of heparin-binding EGF-like growth factor, in human resistant ovarian cancer. Biochem Biophys Res Commun. 2012;422(4):676–80.

    Article  CAS  PubMed  Google Scholar 

  164. Miyata K, Yotsumoto F, Nam SO, Odawara T, Manabe S, Ishikawa T, Itamochi H, Kigawa J, Takada S, Asahara H, Kuroki M, Miyamoto S. Contribution of transcription factor, SP1, to the promotion of HB-EGF expression in defense mechanism against the treatment of irinotecan in ovarian clear cell carcinoma. Cancer Med. 2014;3(5):1159–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Yagi H, Yotsumoto F, Sonoda K, Kuroki M, Mekada E, Miyamoto S. Synergistic anti-tumor effect of paclitaxel with CRM197, an inhibitor of HB-EGF, in ovarian cancer. Int J Cancer. 2009;124(6):1429–39.

    Article  CAS  PubMed  Google Scholar 

  166. Tang XH, Deng S, Li M, Lu MS. Cross-reacting material 197 reverses the resistance to paclitaxel in paclitaxel-resistant human ovarian cancer. Tumour Biol. 2016;37(4):5521–8.

    Article  CAS  PubMed  Google Scholar 

  167. Tang XH, Li H, Zheng XS, Lu MS, An Y, Zhang XL. CRM197 reverses paclitaxel resistance by inhibiting the NAC-1/Gadd45 pathway in paclitaxel-resistant ovarian cancer cells. Cancer Med. 2019;8(14):6426–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Giri S, Rattan R, Deshpande M, Maguire JL, Johnson Z, Graham RP, Shridhar V. Preclinical therapeutic potential of a nitrosylating agent in the treatment of ovarian cancer. PLoS One. 2014;9(6):e97897.

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  169. Shen Y, Ruan L, Lian C, Li R, Tu Z, Liu H. Discovery of HB-EGF binding peptides and their functional characterization in ovarian cancer cell lines. Cell Death Discov. 2019;5:82.

    Article  PubMed  PubMed Central  Google Scholar 

  170. Miyamoto S, Iwamoto R, Furuya A, Takahashi K, Sasaki Y, Ando H, Yotsumoto F, Yoneda T, Hamaoka M, Yagi H, Murakami T, Hori S, Shitara K, Mekada E. A novel anti-human HB-EGF monoclonal antibody with multiple antitumor mechanisms against ovarian cancer cells. Clin Cancer Res. 2011;17(21):6733–41.

    Article  CAS  PubMed  Google Scholar 

  171. Yotsumoto F, Oki E, Tokunaga E, Maehara Y, Kuroki M, Miyamoto S. HB-EGF orchestrates the complex signals involved in triple-negative and trastuzumab-resistant breast cancer. Int J Cancer. 2010;127(11):2707–17.

    Article  CAS  PubMed  Google Scholar 

  172. Nam SO, Yotsumoto F, Miyata K, Fukagawa S, Odawara T, Manabe S, Ishikawa T, Kuroki M, Yasunaga S, Miyamoto S. Anti-tumor effect of intravenous administration of CRM197 for triple-negative breast cancer therapy. Anticancer Res. 2016;36(7):3651–7.

    CAS  PubMed  Google Scholar 

  173. Li H, Duhachek-Muggy S, Qi Y, Hong Y, Behbod F, Zolkiewska A. An essential role of metalloprotease-disintegrin ADAM12 in triple-negative breast cancer. Breast Cancer Res Treat. 2012;135(3):759–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Umemura S, Yoshida S, Ohta Y, Naito K, Osamura RY, Tokuda Y. Increased phosphorylation of Akt in triple-negative breast cancers. Cancer Sci. 2007;98(12):1889–92.

    Article  CAS  PubMed  Google Scholar 

  175. Nishikawa K, Asai T, Shigematsu H, Shimizu K, Kato H, Asano Y, Takashima S, Mekada E, Oku N, Minamino T. Development of anti-HB-EGF immunoliposomes for the treatment of breast cancer. J Control Release. 2012;160(2):274–80.

    Article  CAS  PubMed  Google Scholar 

  176. Okamoto A, Asai T, Hirai Y, Shimizu K, Koide H, Minamino T, Oku N. Systemic administration of siRNA with anti-HB-EGF antibody-modified lipid nanoparticles for the treatment of triple-negative breast cancer. Mol Pharm. 2018;15(4):1495–504.

    Article  CAS  PubMed  Google Scholar 

  177. Okamoto A, Asai T, Kato H, Ando H, Minamino T, Mekada E, Oku N. Antibody-modified lipid nanoparticles for selective delivery of siRNA to tumors expressing membrane-anchored form of HB-EGF. Biochem Biophys Res Commun. 2014;449(4):460–5.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by the Natural Science Foundation of Hubei Province (grant number 2022CFB252); the National Natural Science Foundation of China (grant number 82071655); the cross-innovation talent project in Renmin Hospital of Wuhan University (grant number JCRCZN-2022-016); the undergraduate education quality construction comprehensive reform project (grant number 2022ZG282).

Author information

Author notes

  1. Yuwei Zhang and Lujia Tang contributed equally to this work.

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 99 Zhang Zhidong Road, Wuhan, Hubei, 430060, People’s Republic of China

    Yuwei Zhang, Lujia Tang, Hua Liu & Yanxiang Cheng

Authors
  1. Yuwei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lujia Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hua Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yanxiang Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Yuwei Zhang and Yanxiang Cheng designed this research. Lujia Tang searched the relevant articles. Yuwei Zhang and Lujia Tang drafted the article. Hua Liu and Yanxiang Cheng revised this article. All figures were created with Biorender.com.

Corresponding authors

Correspondence to Hua Liu or Yanxiang Cheng.

Ethics declarations

Ethics Approval

Not applicable.

Consent to Participate

All authors approved of participating in this review.

Consent for Publication

All authors approved of the version to be published.

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, Y., Tang, L., Liu, H. et al. The Multiple Functions of HB-EGF in Female Reproduction and Related Cancer: Molecular Mechanisms and Targeting Strategies. Reprod. Sci. (2024). https://doi.org/10.1007/s43032-024-01454-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s43032-024-01454-6

Keywords

Search

Navigation