2. KNOWN BREAST CANCER RISK FACTORS AND PARADIGMS OF CARCINOGENESIS Perhaps the most consistent risk factor for breast cancer is diagnosis of the disease in a first-degree relative. A positive family history of breast cancer may or may not imply genetic susceptibility, however. It may also be due to similar environments or lifestyle habits, i.e., risk factors that are common to the mother are also common to the daughter(s). It is also possible that familial occurrence due to an inherited susceptibility is heterogeneous in mechanism and strength. Genetic susceptibility may reside in more than one gene locus, i.e., in proto-oncogenes related to signal transduction and cell cycle control, in hormone metabolism or responsiveness, in allelic loss in tumor suppressor genes, or polymorphisms in genes involved in carcinogen metabolism and detoxification, DNA repair, and immune response.
There is considerable clinical and epidemiological evidence to suggest that breast cancer is influenced by hormones, and to a lesser extent environmental exposures. Well-established risk factors for breast cancer include early age at menarche, late age at menopause, late age at first full-term pregnancy, and nulliparity. Body size also appears to influence breast cancer risk, but appears to differ according to menopausal status. High body mass index (BMI) is associated with increased risk of breast cancer among postmenopausal women, but not premenopausal women. Other putative risk factors for breast cancers originate in the environment. The presumed relationship between dietary fat and breast cancer risk has not been supported in most epidemiologic studies. There are somewhat consistent data to suggest that consumption of fruits and vegetables decreases risk, however. There are also consistent data indicating that alcohol consumption, even moderate use, increases risk of breast cancer. Cigarette smoking, despite being a biologically plausible risk factor, has been associated with increased risk of breast cancer only among certain subgroups of women.
There are primarily two paradigms proposed to link the above risk factors to breast carcinogenesis. The historically older model, which has predominated until recently, is that of two-stage carcinogenesis. Based on rodent experiments, this is a model of initiation and promotion; cells that develop mutations through DNA damage replicate and immortalize that damage. In the case of breast cancer, replication would be driven by the mitotic stimulation of circulating steroid hormones. While we now know that there are likely multiple ‘hits’ that damage DNA, and multiple genetic events occurring over a number of years, this model of DNA damage and cell replication is still plausible. There are a number of factors that could initiate DNA damage, including chemical carcinogens, hormone metabolites, spontaneous errors in replication, and reactive oxygen species (ROS) that could be generated through a number of processes.
The second paradigm of carcinogenesis in hormonally responsive tissue asserts that steroid hormones are complete carcinogens. Biosynthesis and metabolism of estrogens is mediated by a number of enzymes, many which are polymorphic. Some estrogen metabolites, namely the 4-hydroxy catechol estrogen, have been shown to bind to DNA and cause mutations. In this scenario, estrogens would act as both the DNA damaging agent and the mitotic stimulator.
The ability to link breast cancer risk factors to mechanisms of carcinogenesis can be enhanced by exploring the role of genetic polymorphisms in the various pathways related to exposure and response in affecting ultimate agents that can damage DNA. Polymorphisms in genes involved in the metabolism of steroid hormones or chemical carcinogens can be related to levels of ultimate reactive intermediates. The identification of genetic variants that might modify associations between exposure and disease has the potential to elucidate risk relationships more clearly, as well as to identify subsets of the population that are most susceptible to certain exposures.