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 somatic perturbations. Cumulative lifetime exposure to bioavailable estradiol links most known risk factors (except radiation) for breast cancer. Based on a series of recent experimental and epidemiologic findings, 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 genetic paths, xenohormones can modify DNA structure or function. As for hormonal paths, two distinct mechanisms can influence the potential for aberrant cell growth: compounds can directly bind with endogenous hormone or growth factor receptors affecting cell proliferation or compounds can modify breast cell proliferation altering the formation of hormone metabolites that influence epithelial-stromal interaction and growth regulation. Beneficial xenohormones, such as indole-3-carbinol, genistein, and other bioflavonoids, may reduce aberrant breast cell proliferation, and influence the rate of DNA repair or apoptosis and thereby influence the genetic or hormonal microenvironments. Upon validation with appropriate in vitro and in vivo studies, biologic markers of the risk for breast cancer, such as hormone metabolites, total bioavailable estradiol, and free radical generators can enhance cancer detection and prevention.
Davis
D L
DL
World Resources Institute, Washington, DC 20006, USA. devra@wri.org
Telang
N T
NT
Osborne
M P
MP
Bradlow
H L
HL
D001943:Breast Neoplasms / Q000209:etiology* / Q000235:genetics*; D004249:DNA Damage; D004967:Estrogens / Q000502:physiology / Q000633:toxicity; D004968:Estrogens, Non-Steroidal / Q000633:toxicity; D005260:Female; D006728:Hormones / Q000502:physiology; D006801:Humans; D008954:Models, Biological; D009376:Neoplasms, Hormone-Dependent / Q000209:etiology* / Q000235:genetics*; D012307:Risk Factors; D015262:Xenobiotics / Q000633:toxicity
D004967:Estrogens; D004968:Estrogens, Non-Steroidal; D006728:Hormones; D015262:Xenobiotics