ANTIPROLIFERATIVE AND ANTIESTROGENIC EFFECTS OF ICI 164,384 AND ICI 182,780 IN 4-OH-TAMOXIFEN-RESISTANT HUMAN BREAST-CANCER CELLS

The effects of the anti-estrogens 4-hydroxytamoxifen (OHTam), ICI 164, 384 and.ICI 182,780 were tested on the MCF-7/LCC2 breast-carcinoma cel l line, which grows significantly in the presence of OHTam and serves as a model for studying anti-estrogen resistance of estrogen-receptor- positive breast cancer. Cell proliferation and cathepsin-D secretion w ere strongly inhibited by either ICI 182,780 or ICI 164,384 alone or I CI 164,384 in combination with 17-beta-estradiol (E2) or OHTam. ICI 16 4,384 alone did not affect the cathepsin-D and pS2 mRNA levels, but an tagonized the stimulatory effects of E2 or OHTam on these 2 mRNAs. OHT am was more effective than E2 in increasing cathepsin-D mRNA levels, s upporting the idea that anti-estrogen-resistant breast cancer continue s to overexpress cathepsin-D. These data show that the steroidal antie strogens ICI 164,384 and ICI 182,780 retain their ability to inhibit c ell proliferation and the estrogen-responsiveness of cathepsin-D and p S2 genes in the OHTam-resistant MCF-7/LCC2 cell line. These pure anti- estrogens may thus be efficient second-line treatments of some Tamoxif en-resistant tumors. (C) 1994 Wiley-Liss, Inc.