Breast Density Influences Tumor Subtypes and Tumor Aggressiveness

Biological distinctions between breast cancer subtypes likely reflect differences in the pathways of tumor development. These distinc-tions often translate to different risk factors contributing to develop-ment of various breast cancer subtypes (1). One biologically relevant manner of distinguishing breast cancer subtypes is according to estrogen receptor (ER), progesterone receptor (PR), and HER2 expression (2–5). Breast cancers that are ER-positive are associated with overexpression of genes in the ER-signaling pathway (6). Triple-negative breast cancers (ie, ER negative, PR negative, and HER2 negative) are most likely to exhibit a basal-like pattern of gene expression, characterized by overexpression of genes in the cell proliferation pathway regulated by cyclin-dependent kinase inhibitor 1A (CDKN1A; also known as p21) and DNA replication pathway (6). HER2-expressing breast cancers (ie, ER negative, PR negative, and HER2 positive) exhibit overexpression of genes in the HER2-signaling pathway (6). Epidemiological studies indicate that reproductive risk factors, such as parity-related factors and age at menarche, and body mass index are more strongly associated with ER- or PR-positive tumors than ER -or PR-negative tumors (1,7–10). ER-negative, particularly triple-negative, breast cancer tends to be diagnosed at an earlier age and disproportionately affects African-American women relative to ER-positive breast cancer (11,12). Additionally, serum levels of bioavailable testosterone are inversely associated with risk of ER-negative breast cancer, whereas circu-lating estradiol levels are positively associated with risk of ER-positive breast cancer in postmenopausal women (13).Mammographic breast density is one of the strongest known risk factors for breast cancer (14–17). The mechanisms through which breast density is positively associated with breast cancer risk are unclear. Breast density has been associated with the amount of collagen, stromal, and epithelial tissues in the breast; suggesting that increased epithelial and fibroblast cellularity and activity in dense tissue may contribute to the positive association between breast density and breast cancer risk (18,19). Characterizing the association between breast density and risk of tumor subtypes may enhance our understanding of how breast density influences breast cancer risk, as well as our understanding of how breast cancer subtypes differ in etiology.Most studies that have evaluated the association between breast density and breast cancer risk by expression of biomarkers in the tumor have reported no difference in the magnitude of the associ-ation between breast density and risk for ER-positive vs ER-negative breast cancer (20–25). Two recent studies (26,27) reported greater mean percent density associated with ER-positive disease than ER-negative disease. The few studies that have evalu-ated the prevalence of high breast density among triple-negative, HER2-positive, and ER-positive invasive cancers or the associa-tion of breast density with triple-negative and HER2-expressing subtypes (24,28) have also reported no differences across subtypes.In this issue of the Journal, Yaghjyan et al. (29) investigated whether breast density is associated with ER, PR, and HER2 subtypes and histopathology characteristics of tumor aggressive-ness in a large case–control study of postmenopausal women within the Nurses’ Health Study. Consistent with previous reports (20–25,28), the results presented in this study (29) indicate that breast density is similarly associated with breast cancer risk regard-less of PR or HER2 status. However, in contrast to previous