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Mechanisms Involved in the Evolution of Progestin Resistance in Human Breast Cancer Cells¹

Department of Biochemistry and Molecular Biology [L. C. M., H. D., M. S. J. W., T. M.] and Department of Physiology [L. J. M.], University of Manitoba, Winnipeg, Manitoba, R3E 0W3 Canada

The emergence of resistant cells reduces the efficacy of many forms of drug therapy in human breast cancer. In order to understand some of the possible mechanisms by which hormonally dependent human breast cancers develop resistance to progestin therapy we have developed a human breast cancer cell line (5-RP) which is resistant to the growth inhibitory effects of progestins in culture. These cells routinely grow in 10 µM medroxyprogesterone acetate (MPA). The cell line was developed from T-47D-5 human breast cancer cells by stepwise selection in increasing concentrations of MPA. The progestin-resistant phenotype was relatively stable as assessed by the removal of MPA from the medium for varying periods of time. 5-RP cells passaged in the absence of MPA were still essentially insensitive to the growth inhibitory effects of MPA for at least 22 passages. Even at 53 passages out of the drug the 5-RP line was still less sensitive than the original T-47D-5 parent line.

Transforming growth factor- (TGF-) and epidermal growth factor (EGF) receptor mRNA were both increased in the 5-RP line compared to the T-47D-5. Consistent with increased TGF- expression, the EGF receptor measured by ligand binding was decreased. When the cells were removed from MPA, TGF- expression declined gradually, but EGF-receptor mRNA levels increased, as did EGF-binding activity.

These cells remained estrogen and progesterone receptor positive. Although progestins did not downregulate estrogen receptor expression, they did downregulate progesterone receptor expression in the 5-RP line. The progesterone receptor level of the 5-RP line, in the absence of MPA, was approximately 58% of that found in T-47D-5 cells, even after MPA had been removed for long periods of time. This decrease in receptor level was reflected in decreased ability to respond to progestins as assessed by the decreased ability of MPA to active expression of both an endogenous gene (EGF receptor) as well as a transiently transfected progestin-responsive gene (MMTV-TK-CAT).

Progestin resistance in the 5-RP cell line appears to be multifactorial, involving both increased growth factor expression and decreased receptor levels. It is likely, however, that these two aspects do not account entirely for the progestin-resistant phenotype and as yet other unidentified mechanisms may also be involved.

¹ This work was supported by grants from the National Cancer Institute (Canada), the Medical Research Council (Canada), and the Manitoba Health Research Council. L. C. M. is a National Cancer Institute (Canada) Scientist, L. J. M. is a Medical Research Council (Canada) Scholar, M. S. J. W. holds a Medical Research Council (Canada) studentship award, and T. M. holds a Manitoba Health Research Council studentship award.

² To whom requests for reprints should be addressed, at Department of Biochemistry and Molecular Biology, University of Manitoba, 770 Bannatyne Avenue, Winnipeg, Manitoba, R3E 0W3, Canada.

Received 2/23/90. Accepted 2/ 4/91.

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