Associations of mammographic breast density with breast stem cell marker-defined breast cancer subtypes

Purpose: High mammographic breast density is a strong, well-established breast cancer risk factor. Whether stem cells may explain high breast cancer risk in dense breasts is unknown. We investigated the association between breast density and breast cancer risk by the status of stem cell markers CD44, CD24, and ALDH1A1 in the tumor. Methods: We included 223 women with primary invasive or in situ breast cancer and 399 age-matched controls from Mayo Clinic Mammography Study. Percent breast density (PD), absolute dense area (DA), and non-dense area (NDA) were assessed using computer-assisted thresholding technique. Immunohistochemical analysis of the markers was performed on tumor tissue microarrays according to a standard protocol. We used polytomous logistic regression to quantify the associations of breast density measures with breast cancer risk across marker-defined tumor subtypes. Results: Of the 223 cancers in the study, 182 were positive for CD44, 83 for CD24 and 52 for ALDH1A1. Associations of PD were not significantly different across t marker-defined subtypes (51% + vs. 11–25%: OR 2.83, 95% CI 1.49–5.37 for CD44+ vs. OR 1.87, 95% CI 0.47–7.51 for CD44−, p-heterogeneity = 0.66; OR 2.80, 95% CI 1.27–6.18 for CD24+ vs. OR 2.44, 95% CI 1.14–5.22 for CD24−, p-heterogeneity = 0.61; OR 3.04, 95% CI 1.14–8.10 for ALDH1A1+ vs. OR 2.57. 95% CI 1.30–5.08 for ALDH1A1−, p-heterogeneity = 0.94). Positive associations of DA and inverse associations of NDA with breast cancer risk were similar across marker-defined subtypes. Conclusions: We found no evidence of differential associations of breast density with breast cancer risk by the status of stem cell markers. Further studies in larger study populations are warranted to confirm these associations.