Mammographic density. Potential mechanisms of breast cancer risk associated with mammographic density: hypotheses based on epidemiological evidence

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Abstract
There is now extensive evidence that mammographic density is an independent risk factor for breast cancer that is associated with large relative and attributable risks for the disease. The epidemiology of mammographic density, including the influences of age, parity and menopause, is consistent with it being a marker of susceptibility to breast cancer, in a manner similar to the concept of 'breast tissue age' described by the Pike model. Mammographic density reflects variations in the tissue composition of the breast. It is associated positively with collagen and epithelial and nonepithelial cells, and negatively with fat. Mammographic density is influenced by some hormones and growth factors as well as by several hormonal interventions. It is also associated with urinary levels of a mutagen. Twin studies have shown that most of the variation in mammographic density is accounted for by genetic factors. The hypothesis that we have developed from these observations postulates that the combined effects of cell proliferation (mitogenesis) and genetic damage to proliferating cells by mutagens (mutagenesis) may underlie the increased risk for breast cancer associated with extensive mammographic density. There is clearly a need for improved understanding of the specific factors that are involved in these processes and of the role played by the several breast tissue components that contribute to density. In particular, identification of the genes that are responsible for most of the variance in percentage density (and of their biological functions) is likely to provide insights into the biology of the breast, and may identify potential targets for preventative strategies in breast cancer.