Breast Density Influences Tumor Subtypes and Tumor Aggressiveness

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Biological distinctions between breast cancer subtypes likely reflect differences in the pathways of tumor development. These distinctions often translate to different risk factors contributing to development 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 circulating estradiol levels are positively associated with risk of ER-positive breast cancer in postmenopausal women ( 13 ).