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Inhibition of cell proliferation by 17β-estradiol and heregulin β1 in estrogen receptor negative human breast carcinoma cell lines

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Abstract

Heregulin (HRG) and 17β-estradiol (E2) interactions that modulate growth of breast cancer cell lines have recently been demonstrated. We examined the ability of heregulin β1 (HRGβ1) and 17β-estradiol to modulate the biological behavior of estrogen receptor (ER) negative human breast cancer cell lines (AU-565). The proliferation of AU-565, MBA-MB231, and SKBR3 cells was additively inhibited by treatment with 17β-estradiol (10-6 M) and HRGβ1 (10 ng/ml). 17-β estradiol did not support the transcriptional activation of a reporter gene construct containing an estrogen response element transfected into AU-565 cells. This finding suggested functional endogenous ER was not present in AU-565 cells. However, the cells contained a high number of low affinity estrogen binding sites. 17β-estradiol only slightly decreased basal tyrosine phosphorylation of ErbB-2 and ErbB-3. Estrogen and HRGβ1 treatment resulted in an increase of c-myc mRNA. We conclude that 17β-estradiol and HRGβ1, in combination, potently inhibit cell proliferation of three ER negative breast carcinoma cell lines.

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References

  1. Evans RM: The steroid and thyroid hormone receptor super-family. Science 240: 889–895, 1988

    Google Scholar 

  2. Gronemeyer H: Transcription activity by estrogen and progesterone receptors. Annu Rev Genet 25: 89–123, 1991

    Google Scholar 

  3. Matsuda S, Kadowaki Y, Ichino M, Akiyama T, Toyoshima K, Yamamoto T: 17β-estradiol mimics ligand activity of the c-ErbB-Z protooncogene product. Proc Natl Acad Sci USA 90: 10803–10807, 1993

    Google Scholar 

  4. Nakhla AM, Khan MS, Romas NP, Rosner W: Estradiol canses the rapid accumulation of cAMP in human prostate. Proc Natl Acad Sci USA 91: 5402–5405, 1994

    Google Scholar 

  5. Aronica SM, Kraus WL, Katzenellenbogen BS: Estrogen action via the cAMP signaling pathway stimulation of adenylate cyclase and cAMP-regulated gene transcription. Proc Natl Acad Sci USA 91: 8517–8521, 1994

    Google Scholar 

  6. Aronica SM, Katzenellenbogen BS: Stimulation of estrogen receptor-mediated transcription and alteration in the phosphorylation state of the rat uterine estrogen receptor by estrogen, cyclic adenosine monophosphate, and insulin-like growth factor-1. Mol Endocrinol 7: 743–751, 1993

    Google Scholar 

  7. Kato S, Endoh H, Masuhiro Y, Kitamoto T, Uchiyama S, Sasaki H, Masushige S, Gotoh Y, Nishida E, Kawashima H, Metzger D, Chambon P: Activation of the estrogen receptor though phosphorylation by mitogen-activated protein kinase. Science 270: 1491–1494, 1995

    Google Scholar 

  8. Ignar-Trowbridge DM, Teng CT, Ross KA, Parker MG, Korach KS, McLachlan JA: Peptide growth factors elicit estrogen receptor-dependent transcriptional activation of an estrogen-responsive element. Mol Endocrinol 7: 992–998, 1993

    Google Scholar 

  9. Akiyama T, Sudo C, Ogawa H, Toyosima K, Yamamoto T.: The product of human c-erbB-2 gene: a 185 kilodalton glycoprotein with tyrosine kinase activity. Science 232: 1644–1646, 1986

    Google Scholar 

  10. Lofts FJ, Gullick WJ: Breast Cancer Cellular and Molecular Biology, Kluwer Academic Publishers, Boston, 1992

    Google Scholar 

  11. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL: Human breast cancer: Correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235: 177–182, 1987

    Google Scholar 

  12. McCann AH, Dervan PA, O'Regan M, Codd MB, Gullick WJ, Tobin BM, Carney DN: Prognostic significance of cerbB-2 and estrogen receptor status in human breast cancer. Cancer Res 51: 3296–3303, 1991

    Google Scholar 

  13. Kallioniemi OP, Holli K, Visakorpi T, Koivula T, Helin HH, Isola JJ: Association of c-erbB-2 protein over-expression with high rate of cell proliferation, increased risk of visceral metastasis and poor long term survival in breast cancer. Int J Cancer 49: 650–655, 1991

    Google Scholar 

  14. Lupu R, Colomer R, Zugmaier G, Sarup J, Shepard M, Slamon D, Lippman ME: Direct interaction of a ligand for the ErbB-2 oncogene product with the EGF receptor and p185ErbB-2. Science 249: 1552–1555, 1990

    Google Scholar 

  15. Holmes WE, Sliwkowski MX, Akita RW, Henzel WJ, Lee G, Park JW, Yansurd D, Abadi N, Raab II, Lewis GD, Shepard HM, Kuang W-J, Wood WI, Goeddel DV, Vandlen RL: Identification of heregulin, a specific activator of p185ErbB-2. Science 256: 1205–1210, 1992

    Google Scholar 

  16. Peles E, Bacus SS, Koski RA, Lu HS, Wen D, Ogden SG, Ben Levy R, Yarden Y: Isolation of the Neu/Her-2 stimulatory ligand: a 44 kd glycoprotein that induces differentiation of mammary tumor cells. Cell 69: 205–216, 1992

    Google Scholar 

  17. Sliwkowski MX, Schaefer G, Akita RW, Lofgren JA, Fitzpatrick VD, Nuijens A, Fendly BM, Cerione RA, Vandlen RL, Carraway KL III: Coexpression of ErbB-2 and ErbB-3 proteins reconstitutes a high affinity receptor for heregulin. J Biol Chem 269: 14661–14665, 1994

    Google Scholar 

  18. Bacus SS, Zelnick CR, Plowman G, Yarden Y: Expression of the erbB-2 family of growth factor receptors and their ligands in breast cancers. Am J Clin Pathol 102(Suppl 1): S13–S24, 1994

    Google Scholar 

  19. Adnane J, Gaudray P, Simon M-P, Simony-Lafontaine L, Jeanteur P, Theillet C: Proto-oncogene amplification and human breast tumor phenotype. Oncogene 4: 1389–1395, 1989

    Google Scholar 

  20. Wright C, Angus B, Nicholson S, Sainsbury JRC, Cairns J, Gullick WJ, Kelly P, Harris AL, Horne CHW: Expression of c-erbB-2 oncoprotein: a prognostic indicator in human breast cancer. Cancer Res 49: 2087–2090, 1989

    Google Scholar 

  21. Stal O, Sullivan S, Sun XF, Wingren S, Nordenskjold B: Simultaneous analysis of c-erbB-2 expression and DNA content in breast cancer using flow cytometry. Cytometry 16: 160–168, 1994

    Google Scholar 

  22. Dati C, Antoniotti S, Taverna D, Perroteau I, De Bortoll M: Inhibition of c-erbB-2 oncogene expression by estrogens in human breast cancet cells. Oncogene 5: 1001–1006, 1990

    Google Scholar 

  23. Russell KS, Hung M-C: Transcriptional repression of the neu protooncogene by estrogen stimulated estrogen receptor. Cancer Res 52: 6624–6629, 1992

    Google Scholar 

  24. Antoniotti S, Maggiora P, Dati C, De Bortoli M: Tamoxifen up-regulates c-erbB-2 expression in estrogen-responsive breast cancer cells in vitro. Eur J Cancer 28: 318–321, 1992

    Google Scholar 

  25. Engel LW, Young NA: Human breast carcinoma cells in continuous culture: a review. Cancer Res 38: 4327–4339, 1978

    Google Scholar 

  26. Bacus SS, Huberman E, Chin D, Kiguchi K, Simpson S, Lippman M, Lupu RA: Ligand for the erbB-2 oncogene product (gp30) induces differentiation of human cancer cells. Cell Growth Differ 3: 401–411, 1992

    Google Scholar 

  27. Bacus SS, Gudkov AV, Zelnick CR, Chin D, Stern R, Stancovski I, Peles E, Ben-Baruch N, Farbstein H, Lupu R, Wen D, Sela M, Yarden Y: Neu differentiation factor (heregulin) induces expression of intercellular adhesion molecule 1: implications for mammary tumor. Cancer Res 53: 5251–5261, 1993

    Google Scholar 

  28. Hamburger AW, Pinnamaneni G: Interferon induced increase in c-myc expression in a human breast carcinoma cell line. Anticancer Res 11: 1891–1894, 1991

    Google Scholar 

  29. Daly JM, Jannot CB, Beerli RR, Graus-Porta D, Maurer FG, Haynes NE: Neu differentiation factor induces ErbB-2 down-regulation and apoptosis of ErbB2-overexpressing breast tumor cells. Cancer Res 57: 3804–3811, 1997

    Google Scholar 

  30. Sommers CL, Byers SW, Thompson EW, Torri JA, Gelmann EP: Differentiation state and invasiveness of human breast cancer cell lines. Breast Cancer Res Treat 31: 325–335, 1994

    Google Scholar 

  31. Kang Y, Cortina R, Perry RR: Role of c-myc in tamoxifen-induced apoptosis in estrogen-independent breast cancer cells. J Natl Cancer Inst 88: 279–284, 1996

    Google Scholar 

  32. Pietras RJ, Arboleda J, Reese DM, Wongvipat N, Pegram MD, Ranos L, Gorman CM, Parker MG, Sliwkowski MX, Slamon DJ: Her-2 tyrosine kinase pathway targets estrogen receptor and promotes hormone-independent growth in human breast cancer cells. Oncogene 10: 2435–2446, 1995

    Google Scholar 

  33. Tang C, Cardillo M, Yang D, Cho C, Watbel C, Perez C, Lupu R: Heregulin β2 isoform induces estrogen-independent tumorigenicity of human breast cancer cells in athymic mice. Proc Amer Assoc Cancer Res 36: 169, 1995

    Google Scholar 

  34. Morrison RS, Gross JL, Herblin WF, Reilly TM, LaSala PA, Alterman RL, Moskal JR, Kornblith PL, Dexter DL: Basic fibroblast growth factor-like activity and receptors are expressed in a human glioma cell line. Cancer Res 50: 2524–2529, 1990

    Google Scholar 

  35. Chen X, Levkowitz G, Tzahar E, Karunagaran D, Lavi S, Ben Baruch N, Leitner O, Ratzkin BJ, Bacus SS, Yarden Y: An immunological approach reveals biological differences between the two NDF/heregulin receptors, ErbB-3 and ErbB-4. J Biol Chem 271: 7620–7629, 1996

    Google Scholar 

  36. Evan GI, Wyllie AH, Gilbert CS, Littlewood TD, Land H, Brooks M, et al.: Induction of apoptosis in fibroblasts by c-myc protein. Cell 59: 119–128, 1992

    Google Scholar 

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Yoo, JY., Lessor, T. & Hamburger, A.W. Inhibition of cell proliferation by 17β-estradiol and heregulin β1 in estrogen receptor negative human breast carcinoma cell lines. Breast Cancer Res Treat 51, 71–81 (1998). https://doi.org/10.1023/A:1006035603635

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