Mammographic breast density may be the most undervalued and underused risk factor in studies investigating breast cancer.13,38,73 It is a heritable trait, although the contribution of breast density to increased risk is independent of the risk associated with BRCA1 and BRCA2 mutations.7 Despite the ethnic variation in breast density, breast cancer risk rises with increasing breast density for each of the ethnic groups recently analyzed by Ursin and colleagues; the groups they analyzed included African Americans, Asian Americans, and non-Latino whites.69 A 2002 study reported that the average relative risk of breast cancer for women in the highest category of percentage of dense tissue compared with those in the lowest category is about 4.7 Previous studies reported relative risk estimates ranging from 2 to 6, with the majority of those studies reporting a relative risk of 4 or more (reviewed by Boyd and colleagues, 2002).7 The genetic factors that determine breast density may also play a role in breast cancer.73
Before a cell becomes cancerous, it must accumulate a “critical mass” of molecular changes that alter key genes or their functions. The end result is a loss of the normal molecular controls on the cell’s growth and differentiation. Some of the cellular changes that make a woman susceptible to developing breast cancer can be inherited. Such germ-line mutations are believed to account for the striking incidence of breast cancer in certain families, especially breast cancer that develops in both a woman’s breasts and/or at a young age. But less than 10 percent of all breast cancer cases are thought to stem from inherited mutations, such as BRCA1 and BRCA2, that individually increase risk by a substantial amount.41
The majority of breast cancer cases are due to an accumulation of cellular (somatic) changes that occur during a patient’s lifetime. This is why age is such a significant factor in most cancers—because the longer a person lives, the more time there is for mutations to accumulate. These changes are not inherited, but rather stem from factors such as exposure to carcinogens in the external environment, or from excessive or untimely exposure to breast cancer-promoting substances within the body, such as circulating hormones, or simply because of random mutations that occur during cell division. Inherited genes can also influence genetic mutations that occur during a person’s lifetime if they increase the susceptibility of other genes to mutation. For example, the ability of a cell to correct mistakes in gene replication that occur during cell division is diminished when the genes that normally support DNA repair have mutated. As a result, mutations accumulate faster than they would otherwise.