Hormonal carcinogenesis

Hormone-related cancers, namely breast, endometrium, ovary, prostate, testi s, thyroid and osteosarcoma, share a unique mechanism of carcinogenesis. En dogenous and exogenous hormones drive cell proliferation, and thus the oppo rtunity for the accumulation of random genetic errors. The emergence of a m alignant phenotype depends on a series of somatic mutations that occur duri ng cell division, but the specific genes involved in progression of hormone -related cancers are currently unknown. In this review, the epidemiology of endometrial cancer and breast cancer are used to illustrate the paradigms of hormonal carcinogenesis. Then, new strategies for early detection and pr evention of hormonal carcinogenesis are discussed, This includes developing polygenic models of cancer predisposition and the further development of s afe and effective chemopreventives that block target sequence activity. We developed polygenic models for breast and prostate cancer after hypothesizi ng that functionally relevant sequence variants in genes involved in steroi d hormone metabolism and transport mould act together, and also interact wi th well-known hormonally related risk factors, to define a highrisk profile for cancer. A combination of genes each with minor variation in expressed activity could provide a degree of separation of risk that would be clinica lly useful as they could yield a large cumulative difference after several decades. The genes included in the breast cancer model are the 17 beta-hydr oxysteroid dehydrogenase 1 (HSD17B1) gene, the cytochrome P459c17 alpha (CY P17) gene, the aromatase (CYP19) gene, and the estrogen receptor alpha (ER) gene. The prostate cancer model includes the androgen receptor gene (AR), steroid 5 alpha-reductase type II (SRD5A2), CYP17 and the 3 beta hydroxyste roid dehydrogenase (HSD3B2) gene. We present data from our multi-ethnic coh ort to support these models.