Estrogen and oncogene mediated growth regulation of human breast cancer cells

Abstract

The mechanism of growth control in estrogen-dependent and -independent human breast cancer is not completely understood. We have used both hormonally responsive and unresponsive breast cancer cells in culture to study the role of estrogens, oncogenes, and growth factors in their malignant transformation. MCF-7, an estrogen-receptor containing cell line, requires estradiol for tumor formation in vivo and is growth stimulated by estradiol and growth inhibited by antiestrogens in vitro. The growth regulation of MCF-7 cells by estrogens and antiestrogens may be linked to changes in several growth-related enzymes and polypeptide growth factors. Growth-acting polypeptides that are estradiolinducible include IGF-I, TGF-α, and PDGF. Induction of at least two growth-related enzymes, thymidine kinase and dihydrofolate reductase is by transcriptional regulation of their mRNAs. To understand the natural progression of human breast cancer, we have experimentally constructed a hormone-independent fully tumorigenic cell line from the non-tumorigenic MCF-7 cells by introduction of an activated oncogene, v-ras h , into these cells by DNA-mediated gene transfer. Acquisition of the activated ras gene confers hormone autonomy on the previously hormone-dependent tumorigenicity and results in upregulation in secretion of some of the growth factors in amounts compared to estradiol stimulation. The transfected cells also become refractory to growth regulation by estradiol and antiestrogens in culture, although estrogen responses persist. Hormone-independent breast cancer cells in culture show high constitutive growth factor secretion. Direct infusion of some of the authentic growth factors and medium conditioned by estrogen-independent cells into athymic ovariectomized mice suggests a direct involvement of some of the polypeptides in the in vivo progression of tumors by these cells. Thus, aberrant production of growth factors, triggered either by activated oncogenes and estrogen stimulation in hormone-dependent cells, or by increased constitutive production in hormone-independent cells may in an autocrine, paracrine, or endocrine manner be associated with neoplastic growth of breast cancer.