EFFECT OF P-GLYCOPROTEIN EXPRESSION ON SENSITIVITY TO HORMONES IN MCF-7 HUMAN BREAST-CANCER CELLS

Background: Data obtained from studies of primary human breast cancers and established cell lines indicate that overexpression of the MDR1 gene (also known as PGY1) is associated with decreased expression of steroid hormone receptors and increased expression of epidermal growth factor (EGF) receptors. Other study results indicate that both progestins and triphenylethylene antiestrogens may be substrates for P-glycoprotein, the product of the MDR1 gene. These findings together suggest an association between overexpression of the MDR1 gene and cross-resistance to progestin and antiestrogen therapies. Purpose: This study was designed to determine (a) the ability of MDR1 expression to alter tumor sensitivity to hormone therapy and (b) the role of MDR1 expression in expression of functional hormone receptors in human breast cancer. Methods: We transduced MCF-7 cells with MDR1 complementary DNA, using a retroviral vector directing the constitutive expression of the MDR1 gene. Transduced cells (MCF-7MDR1) were examined for ability to produce P-glycoprotein, expression of steroid hormone receptors, and responsivity to antiestrogens. For comparison, we used MCF-7ADR human breast cancer cells, which overexpress MDR1 and have also lost the requirement for 17beta-estradiol supplementation to form tumors in nude mice. We also investigated the level of EGF-R mRNA expression by using a sensitive RNase protection analysis. Results: MCF-7MDR1 cells retained both estrogen receptor and progesterone receptor expression as well as sensitivity to 4-hydroxytamoxifen. Expression of the estrogen-inducible pS2 and EGF receptor genes was similar in parental MCF-7 and transduced MCF-7MDR1 cells. EGF receptor expression was increased, and pS2 expression was lost (undetectable) in MCF-7ADR cells. Conclusions: The data indicate that overexpression of the MDR1 gene alone confers a multidrug-resistant phenotype, but it does not directly result in either cross-resistance to antiestrogens or a loss of steroid hormone receptor expression. Implications: MCF-7MDR1 cells provide an important model for study of the interactions of cytotoxic drugs, hormones, and the MDR1 glycoprotein in human hormone-responsive breast cancer cells.