Oncogenic BRCA1,2 Mutations in the Human Lineage-A By-Product of Sexual Selection?

Abstract

In this review, we discuss the long-known problem of tissue-specific carcinogenesis in BRCA1 and BRCA2 mutation carriers: while the genes are expressed ubiquitously, increased cancer risk is observed mostly in the breast and ovaries, and to a much lesser extent, in some other tissues such as the prostate or pancreas. We reevaluate hypotheses on the evolutionary origin of these mutations in humans. Also, we align together the reports that at least some great apes have much lower risks of epithelial cancers in general and breast cancer in particular with the fact that humans have more voluminous breast tissue as compared to their closest extant relatives, particularly chimpanzees and bonobos. We conjecture that this disparity may be a consequence of sexual selection, augmented via selection for enhanced lactation. Further, we argue that there is an organ-specific enigma similar to the Peto paradox: breast cancer risk in humans is only minimally correlated with breast size. These considerations lead to the hypothesis that, along with the evolutionary development of larger breasts in humans, additional changes have played a balancing role in suppressing breast cancer. These yet-to-be-discovered mechanisms, while purely speculative, may be valuable to understanding human breast cancer, though they may not be exclusive to the mammary gland epithelial cells. Combining these themes, we review some anti-carcinogenesis preventive strategies and prospects of new interventions against breast cancer.

Keywords: breast cancer; estrogens; evolution; mastectomy; sexual selection.

Figure 1

BRCA tissue-specificity paradox. BRCA1 and BRCA2 haploinsufficiency increases the risks for breast, ovarian, and pancreatic cancers despite ubiquitous expression in all tissues.

Figure 2

Breast cancer risk and the enigma of breast size versus breast cancer incidence similar to Peto paradox. Theoretically, larger breast size should indicate an increased breast cancer risk. This is true, but in a surprisingly small degree.