REGULATION OF THE LEVELS OF 3 TRANSFORMING GROWTH-FACTOR-BETA MESSENGER-RNAS BY ESTROGEN AND THEIR EFFECTS ON THE PROLIFERATION OF HUMAN BREAST-CANCER CELLS

Transforming growth factor (TGF) beta is a potent regulator of cell proliferation and may play a role in breast cancer cell growth. We have evaluated the regulation of TGF beta 1, TGF beta 2, and TGF beta 3 mRNAs by 17 beta-estradiol (E(2)) and 4-hydroxytamoxifen (MOH) in estrogen receptor-positive (ER(+)) MCF-7 and estrogen receptor-negative (ER(-)) MDA-MB-231 human breast cancer cells. We also determined the effect of TGF beta 1, TGF beta 2, and TGF beta 3 on the proliferation of these cells. Cells were deprived of estrogen before the addition of hormones. and mRNA was measured by Northern blot analysis. We found that MCF-7 cells expressed mRNAs of all three TGF beta species. Treatment of MCF-7 cells with 10(-10) M E(2) for 7 days resulted in a dramatic decrease in the TGF beta 2 and TGF beta 3 mRNA levels, but not in the TGF beta 1 mRNA lever: MOH was found to block these effects. In addition, the regulation of TGF beta 2 and beta 3 gene expression occurs at both transcriptional and post-transcriptional levels. There is an inverse correlation between E(2)-induced growth and levels of TGF beta 2 and TGF beta 3 mRNA. In contrast to MCF-7 cells, MDA-MB-231 cells expressed TGF beta 1 and TGF beta 2 mRNAs but TGF beta 3 mRNA was not detected, and the TGF beta 1 and TGF beta 2 mRNAs were not regulated by estrogens or antiestrogens. TGF beta 3 gene is present in MDA-MB-231 cells and based on the enzymes used, no restriction fragment length polymorphism (RFLP) was observed in the TGF beta 3 gene between the MCF-7 and MDA-MB-231 cells. The addition of TGF beta 1, TGF beta 2, or TGF beta 3 inhibited the growth of MDA-MB-231 but not the late passage of MCF-7 cells. interestingly, the growth of early passage of MCF-7 cells was inhibited by the addition of TGF beta 1, TGF beta 2, or TGF beta 3. In summary, E(2) can regulate the expression of different members of the TGF beta family; however, these may not be directly involved in the E(2)-stimulated proliferation in the late passage of MCF-7 human breast cancer cells. It is possible that paracrine mechanism in regulating cell replication of ER(-) cells is more important for the function of TGF beta in ER(+) MCF-7 cells in response to E(2).