Estrogen promotes chemotherapeutic drug resistance by a mechanism involving bcl-2 proto-oncogene expression in human breast cancer cells

• Published in: Cancer research (Chicago, Ill.) Vol. 55; no. 17; pp. 3902 - 3907
• Main Authors: TEIXEIRA, C, REED, J. C, PRATT, M. A. C
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.09.1995
• Subjects: Antineoplastic agents; Apoptosis; bcl-2-Associated X Protein; Biological and medical sciences; Breast Neoplasms - chemistry; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Doxorubicin - pharmacology; Drug Resistance; Estradiol - analogs & derivatives; Estradiol - pharmacology; Estrogens - pharmacology; General aspects; Humans; Medical sciences; Neoplasms, Hormone-Dependent - chemistry; Neoplasms, Hormone-Dependent - drug therapy; Neoplasms, Hormone-Dependent - genetics; Neoplasms, Hormone-Dependent - metabolism; Pharmacology. Drug treatments; Polyunsaturated Alkamides; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-bcl-2; RNA, Messenger - metabolism; Tumor Cells, Cultured; Antineoplastic agent; Human; Estrogen; Malignant tumor; Gene expression; In vitro; Mechanism; Resistance; Mammary gland diseases; Regulation(control); Cell death; C-Onc gene; Established cell line; Mammary gland; Sex steroid hormone; Tumor cell; Protooncogene
• ISSN: 0008-5472; 1538-7445

Recent studies have shown that the Bcl-2 protein suppresses programmed cell death or apoptosis induced by a variety of stimuli including chemotherapeutic drugs. Because estrogen promotes the survival of estrogen-dependent breast cancer cells in vivo, we investigated whether estrogen might regulate levels of Bcl-2 gene expression in an estrogen-responsive human breast cancer cell line. Estrogen receptor-positive MCF-7 human breast cancer cells cultured in the presence of estrogen express the 8.5-kb Bcl-2 mRNA transcript. Depletion of estrogen from the medium results in loss of expression of the mRNA, whereas reexposure to estrogen markedly induces the Bcl-2 transcript. The changes in Bcl-2 mRNA are paralleled by changes in Bcl-2 protein levels. Estrogen-induced increases in Bcl-2 are significantly inhibited by inclusion of the pure antiestrogen ICI 164,384 in the medium. The Bax protein that heterodimerizes with Bcl-2 and promotes cell death is expressed in MCF-7 cells grown in the presence of estrogen and is unaffected by culture in estrogen-free medium. Estrogen depletion doubles the sensitivity of MCF-7 cells to the cytotoxic effects of Adriamycin compared with cells cultured in medium supplemented with estrogen, consistent with a decrease in the Bcl-2 levels. MCF-7 cells treated simultaneously with estrogen and ICI 164,384 exhibit markedly lower resistance to Adriamycin compared with cells treated with estrogen alone. In the absence of estrogen, MCF-7 cells transfected with Bcl-2 expression plasmids display a marked increase in resistance to Adriamycin. In the presence of estrogen, MCF-7 cells expressing Bcl-2 antisense transcripts are rendered twice as sensitive to acute Adriamycin cytotoxicity as a control clone. We conclude that estrogen can promote resistance of estrogen receptor bearing human breast cancer cells to chemotherapeutic drugs through a mechanism that involves regulation of the Bcl-2 proto-oncogene.