HORMONAL CARCINOGENESIS IN BREAST-CANCER - CELLULAR AND MOLECULAR STUDIES OF MALIGNANT PROGRESSION

We have established and characterized a series of variant cell lines i n which to identify the critical factors associated with E2-induced ma lignant progression, and the acquisition to tamoxifen resistance in hu man breast cancer. Sublines of the hormone-dependent MCF-7 cell line ( MCF7/MIII and MCF7/LCC1) form stable, invasive, estrogen independent t umors in the mammary fat pads of ovariectomized athymic nude mice. The se cells retain expression of both estrogen (ER) and progesterone rece ptors (PGR), but retain sensitivity to each of the major structural cl asses of antiestrogens. The tamoxifen-resistant MCF7/LCC2 cells retain sensitivity to the inhibitory effects of the steroidal antiestrogen I CI 182780. By comparing the parental hormone-dependent and variant hor mone-independent cells, we have demonstrated an altered expression of some estrogen regulated genes (PGR, pS2, cathepsin D) in the hormone-i ndependent variants. Other genes remain normally estrogen regulated (E R, laminin receptor, EGF-receptor). These data strongly implicate the altered regulation of a specific subset or network of estrogen regulat ed genes in the malignant progression of human breast cancer. Some of the primary response genes in this network may exhibit dose-response a nd induction kinetics similar to pS2, which is constitutively upregula ted in the MCF7/MIII, MCF7/LCC1 and MCF7/LCC2 cells.