Progress in clinical and biological research最新文献

Organochlorine industrial compounds, combustion products and pesticides have been widely identified in the environment and residues have been detected in extracts prepared from fish, wildlife, human tissues as well as human milk and serum. Many of these compounds possess sex steroid activities and therefore have the potential to disrupt endocrine-regulated homeostasis. Organochlorines which exhibit hormonal activity include: (i) polychlorinated biphenyls (PCBs), hydroxylated PCBs, o,p'-DDT, and other organochlorine insecticides which exhibit estrogen receptor (ER) agonist activities; (ii) p,p'-DDE, a ligand for the androgen receptor which exhibits antiandrogen activity; (iii) PCBs, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and related aromatic hydrocarbons which bind the aryl hydrocarbon (Ah) receptor and exhibit tissue-specific antiestrogenic activity; and (iv) hydroxylated aromatics which bind transthyretin, a thyroid hormone binding protein. Although, it has been suggested that the estrogenic activity of PCBs and DDE may be a contributing factor for development of breast cancer in women, levels of these compounds are not consistently elevated in breast cancer patients and there is no evidence that women occupationally-exposed to relatively high levels of PCBs or DDE exhibit an increased incidence of breast cancer. In contrast, epidemiology studies suggest that women exposed to high levels of TCDD during an industrial accident in Seveso, Italy, have a decreased incidence of both breast and endometrial cancer. Based on the dietary intake of hormone or antihormone mimics derived from natural compounds in food, the estrogenic contribution of organochlorine compounds is small and their role in development of breast cancer is questionable.

Numerous factors have been noted to be associated with risk of breast cancer. Indicators of endogenous hormonal alterations are among them: early age at menarche and late age at menopause, nulliparity, late age at first full term pregnancy and obesity in postmenopausal women. Other established risk factors are family history of breast cancer, histologic characteristics of benign tissue, mammographic patterns, exogenous hormones and alcohol consumption. Endogenous indicators may be a reflection of enhanced susceptibility, whereas exogenous exposures can have both independent effects on risk and the ability to interact with markers of inherited susceptibility. In case control studies of breast cancer, family history confers a risk elevation of two to three fold. The higher risk estimate occurs when first degree rather than second degree relatives are affected, or if more than one relative is affected. A relative diagnosed before age 45 increases risk for early-onset breast cancer. These findings have been obtained using either traditional analytic methods for case control data or an alternative strategy, which uses case control status as the predictor variable and models the risk to relatives in a time-dependent fashion. Risk of breast cancer is greater for the mother and sisters of cases than controls. The magnitude of risk increases with 1) decreasing age of diagnosis of the index case 2) additional family members with diagnosed breast cancer and 3) bilateral breast cancer in the index case. Although these two analytic approaches have somewhat different data requirements and may be subject to different biases, the results produced are quite consistent. Mutated p53 in female family members of patients with Li-Fraumeni syndrome was one of the first identified genetic susceptibility markers for breast cancer. Application of segregation and linkage analyses to pedigrees with multiple affected family members successfully focused the search for BRCA1. Recent cloning and sequencing of BRCA1 will allow for its use in risk assessment, diagnostic evaluation and screening of high risk women. BRCA1 appears to be primarily responsible for early-onset breast cancer in high risk families. Rare alleles of H-ras could account for some of the late-onset cases in unselected populations since at least 85% of breast cancer appears to be sporadic, other genetic markers yet to be identified undoubtedly exist.