Biochemical Mechanisms Related To Risk Factors Of Mammary Carcinogenesis

Environmental Health Sciences

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Abstract

Many epidemiological and laboratory studies over the past four decades have led investigators to believe that ovarian steroid hormones are permissive or causal factors for cancers of the breast and uterus in women. Although little is known about the mechanisms by which these steroids increase cancer risk in target organs, the potent mitogenic action of these compounds might somehow cause perturbations in the machinery of cell division that result in genomic instability. This "genomic" effect could be created by inappropriate level or extent of hormone exposure. Exposure of postmenopausal women to "unopposed" extrogens is a well-known risk factor for endometrial carcinoma. This laboratory has studied growth factor signaling pathways that are activated by estrogens in the mammary gland and uterus. We have also studied signaling pathways that are constitutively activated in mammary tumors and derived cell lines. IGF-1 and ErbB (ErbB1/ErbB2) signaling were critical for estradiol-stimulated mouse mammary ductal morphogenesis. We also recently described an autocrine/paracrine proliferative pathway in mouse mammary tumor cells that consisted of the heregulin ligand and the ErbB2/ErbB3 receptors. In the period covered by this report, we used a mouse uterine model to investigate how activation of the IGF-1 receptor and its docking protein, insulin receptor substrate (IRS)-1, by estradiol stimulates mitosis in uterine epithelial cells. Mice with a null mutation for IRS-1 exhibit reduced estrogen-stimulated mitosis in uterine epithelial cells when compared to wild-types; the mutation did not affect the incorporation of BrdU. The reduced mitosis observed in the mutants corresponded to lower levels of cyclin B-associated kinase activity in these animals. Our experimental findings suggest that IGF-1/IRS-1 stimulates an Akt/mTOR pathway important for translation of cdk-1, the kinase associated with cyclin B. The regulation of cdk-1 translation by such a signaling cascade may be a common mechanisms used to stimulate mitosis in a wide variety of mammalian cells.