Reproductive factors and expression of stem cell markers in women with incident benign breast disease

Reproductive factors are well-established risk factors for breast cancer. The prevailing hypothesis suggested that stem cell changes may be the key underlying mechanisms, but epidemiological evidence has been notably scarce. Herein we examined the relationship between reproductive risk factors and the expression of well-established stem cell markers CD44, CD24, and ALDH1A1 in benign breast biopsy non-cancerous samples. Our study included 735 participants from the Nurses' Health Study II who were diagnosed with biopsy-confirmed incident benign breast disease (BBD). Reproductive history and other BBD/breast cancer risk factors were measured from self-reported biennial questionnaires. Immunohistochemistry was performed on breast tissue microarrays from normal terminal ductal-lobular units (TDLU) cores. Marker expression in epithelium and stroma was quantified using semi-automated image analysis. The generalized linear regression was used to examine the associations of reproductive factors with the positive expression of CD44, CD24, and ALDH1A1, adjusted for known breast cancer risk factors. Age at first birth ≥30 years old (vs. <25 years) was associated with lower ALDH1A1 expression in the epithelium (β for ≥30 vs. <25 years = -0.30, 95% CI -0.57; -0.03, p-trend = 0.03). Parity, breastfeeding, age at menarche, and the time interval between menarche and age at first birth were not associated with the expression of any of the three markers in epithelium or stroma. These findings suggest age at first birth may influence the ALDH1A1 expression in breast tissue. Our study added to the very limited evidence regarding the potential impact of reproductive factors on breast stem cell markers.