This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Herman, M. E. Articles by Katzenellenbogen, B. S. Search for Related Content PubMed PubMed Citation Articles by Herman, M. E. Articles by Katzenellenbogen, B. S.

Alterations in Transforming Growth Factor- and -ß Production and Cell Responsiveness during the Progression of MCF-7 Human Breast Cancer Cells to Estrogen-Autonomous Growth¹

Department of Physiology and Biophysics, University of Illinois and University of Illinois College of Medicine, Urbana, Illinois 61801

Hormonal management of breast cancer is confounded by an almost inevitable progression of cell growth from a steroid-regulated to a steroid-autonomous state. We have experimentally induced this progression in the estrogen growth-responsive MCF-7 human breast cancer cell line by long-term culture in the absence of steroids. After an initial period (10–12 weeks) of slowed growth in response to steroid deprivation, rapid, steroid-independent growth rates were consistently established. In these cells, which contained 3-fold elevated, functional estrogen receptor levels (as determined by induction of PgR and transactivation of a transiently transfected estrogen-responsive gene construct), antiestrogens still effectively suppressed cell proliferation, although estrogens only minimally increased the proliferation rate. Depletion of steroids from the growth media also resulted in a marked (70–80%) transient decrease in transforming growth factor (TGF) mRNA and TGF- protein production at 2 weeks that was followed by a progressive, partial return to the initial parental TGF- mRNA and protein levels. In contrast, the mRNAs for TGF-ß1,-ß2, and -ß3 and bioactive TGF-ß proteins transiently increased (3–10-fold) at 2 to 10 weeks of steroid deprivation and then returned by 24 weeks to the lower levels of the parental MCF-7 cells. These results suggest that the cells acquired steroid-independent means to regulate the production of these peptides. The long-term steroid-deprived sublines showed a loss of regulation of proliferation by TGF- or anti-TGF- antibodies and a 10-fold decrease in sensitivity to the growth-suppressive effects of TGF-ß1, despite little change in receptor levels for these factors. The diminished contributions of TGF- and TGF-ßs to the regulation of cell proliferation in long-term steroid-deprived MCF-7 breast cancer cells suggest that the TGFs do not act as major growth regulators in these estrogen-autonomous sublines. However, the marked, transient alterations in the levels of these growth factors indicate that they may play a role in the events which accompany the progression from estrogen-responsive to estrogen-autonomous growth. In addition, continued exposure to estrogen may be needed for the long-term maintenance of cell responsiveness to these TGFs.

¹ Supported in part by NIH Grants CA18119 and CA51482 (to B. S. K.), predoctoral fellowship GM07283, and Carle Foundation Cancer Research Funds (to M. E. H.), and a Susan G. Komen Foundation grant.

² To whom requests for reprints should be addressed, at Department of Physiology and Biophysics, University of Illinois, 524 Burrill Hall, 407 S. Goodwin Ave., Urbana, IL 61801.

Received 6/30/94. Accepted 9/29/94.

This article has been cited by other articles:

				J. D. Stender, J. Frasor, B. Komm, K. C. N. Chang, W. L. Kraus, and B. S. Katzenellenbogen Estrogen-Regulated Gene Networks in Human Breast Cancer Cells: Involvement of E2F1 in the Regulation of Cell Proliferation Mol. Endocrinol., September 1, 2007; 21(9): 2112 - 2123. [Abstract] [Full Text] [PDF]

				R I Nicholson, C Staka, F Boyns, I R Hutcheson, and J M W Gee Growth factor-driven mechanisms associated with resistance to estrogen deprivation in breast cancer: new opportunities for therapy Endocr. Relat. Cancer, December 1, 2004; 11(4): 623 - 641. [Abstract] [Full Text] [PDF]

				A. S. Oh, L. A. Lorant, J. N. Holloway, D. L. Miller, F. G. Kern, and D. El-Ashry Hyperactivation of MAPK Induces Loss of ER{alpha} Expression in Breast Cancer Cells Mol. Endocrinol., August 1, 2001; 15(8): 1344 - 1359. [Abstract] [Full Text] [PDF]

				W.-S. Shim, M. Conaway, S. Masamura, W. Yue, J.-P. Wang, R. Kumar, and R. J. Santen Estradiol Hypersensitivity and Mitogen-Activated Protein Kinase Expression in Long-Term Estrogen Deprived Human Breast Cancer Cells in Vivo Endocrinology, January 1, 2000; 141(1): 396 - 405. [Abstract] [Full Text] [PDF]

				C. L. Arteaga, K. M. Koli, T. C. Dugger, and R. Clarke Reversal of Tamoxifen Resistance of Human Breast Carcinomas In Vivo by Neutralizing Antibodies to Transforming Growth Factor-ß J Natl Cancer Inst, January 6, 1999; 91(1): 46 - 53. [Abstract] [Full Text] [PDF]

				M.-H. Jeng, M. A. Shupnik, T. P. Bender, E. H. Westin, D. Bandyopadhyay, R. Kumar, S. Masamura, and R. J. Santen Estrogen Receptor Expression and Function in Long-Term Estrogen-Deprived Human Breast Cancer Cells Endocrinology, October 1, 1998; 139(10): 4164 - 4174. [Abstract] [Full Text] [PDF]

				M. J. Gerdes, M. Larsen, L. McBride, T. D. Dang, B. Lu, and D. R. Rowley Localization of Transforming Growth Factor-b1 and Type II Receptor in Developing Normal Human Prostate and Carcinoma Tissues J. Histochem. Cytochem., March 1, 1998; 46(3): 379 - 388. [Abstract] [Full Text]

				T. A. Guise and G. R. Mundy Cancer and Bone Endocr. Rev., February 1, 1998; 19(1): 18 - 54. [Abstract] [Full Text]

				A. M. Hales, C. G. Chamberlain, C. R. Murphy, and J. W. McAvoy Estrogen Protects Lenses against Cataract Induced by Transforming Growth Factor-beta (TGFbeta ) J. Exp. Med., January 20, 1997; 185(2): 273 - 280. [Abstract] [Full Text] [PDF]