MEDICAL HYPOTHESIS - BIFUNCTIONAL GENETIC-HORMONAL PATHWAYS TO BREAST-CANCER

As inherited germ line mutations, such as loss of BRCA1 or AT, account for less than 5% of all breast cancer, most cases involve acquired so matic perturbations. Cumulative life time exposure to bioavailable est radiol links most known risk factors (except radiation) for breast can cer. Based on a series of recent experimental and epidemiologic findin gs, we hypothesize that the multistep process of breast carcinogenesis results from exposure to endogenous or exogenous hormones, including phytoestrogens that directly or indirectly alter estrogen metabolism. Xenohormones are defined as xenobiotic materials that modify hormonal production; they can work bifunctionally, through genetic or hormonal paths, depending on the periods and extent of exposure. As for generic paths, xenohormones can modify DNA structure or function. As for horm onal paths, two distinct mechanisms can influence the potential for ab errant cell growth: compounds can directly bind with endogenous hormon e or growth factor receptors affecting cell proliferation or compounds can modify breast cell proliferation altering the formation of hormon e metabolites that influence epithelial-stromal interaction and growth regulation. Beneficial xenohormones, such as indole-3-carbinol, genis tein, and other bioflavonoids, may reduce aberrant breast cell prolife ration, and influence the rate of DNA repair or apoptosis and thereby influence the genetic or hormonal microenvironments. Upon validation w ith appropriate in vitro and in vivo studies, biologic markers of the risk for breast cancer, such as hormone metabolites, total bioavailabl e estradiol, and free radical generators can enhance cancer detection and prevention.