ALTERATIONS IN TRANSFORMING GROWTH FACTOR-ALPHA AND FACTOR-BETA PRODUCTION AND CELL RESPONSIVENESS DURING THE PROGRESSION OF MCF-7 HUMAN BREAST-CANCER CELLS TO ESTROGEN-AUTONOMOUS GROWTH

Hormonal management of breast cancer is confounded by an almost inevit able progression of cell growth from a steroid-regulated to a steroid- autonomous state. We have experimentally induced this progression in t he estrogen growth-responsive MCF-7 human breast cancer cell line by l ong-term culture in the absence of steroids. After an initial period ( 10-12 weeks) of slowed growth in response to steroid deprivation, rapi d, steroid-independent growth rates were consistently established. In these cells, which contained 3-fold elevated, functional estrogen rece ptor levels (as determined by induction of PgR and transactivation of a transiently transfected estrogen-responsive gene construct), antiest rogens still effectively suppressed cell proliferation, although estro gens only minimally increased the proliferation rate. Depletion of ste roids from the growth media also resulted in a marked (70-80%) transie nt decrease in transforming growth factor (TGF) alpha mRNA and TGF-alp ha protein production at 2 weeks that was followed by a progressive, p artial return to the initial parental TGF-alpha mRNA and protein level s. In contrast, the mRNAs for TGF-beta 1, -beta 2, and -beta 3 and bio active TGF-beta proteins transiently increased (3-10-fold) at 2 to 10 weeks of steroid deprivation and then returned by 24 weeks to the lowe r levels of the parental MCF-7 cells. These results suggest that the c ells 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-alpha or anti-TGF-alpha antibodi es and a 10-fold decrease in sensitivity to the growth-suppressive eff ects of TGF-beta 1, despite little change in receptor levels for these factors. The diminished contributions of TGF-alpha and TGF-beta s 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 growt h regulators in these estrogen-autonomous sublines. However, the marke d, transient alterations in the levels of these growth factors indicat e that they may play a role in the events which accompany the progress ion from estrogen-responsive to estrogen-autonomous growth. In additio n, continued exposure to estrogen may be needed for the long-term main tenance of cell responsiveness to these TGFs.