Stallings-Mann, ML

Abstract Background: Age-related lobular involution (LI) is a physiological process, usually accelerated with menopause, in which the epithelial tissue of the breast gradually regresses. Our previous analysis of a cohort of more than 14,000 women who had a benign breast biopsy at the Mayo Clinic revealed that women who had undergone LI were at significantly reduced risk of subsequent breast cancer development. In our studies of postmenopausal women specifically, we found that more than 40% had not completed the process of LI, and that the increased breast cancer incidence in older women was strongly associated with incomplete LI. We sought to determine the potential protective mechanistic effects of lobular involution. Methods: We generated primary human mammary epithelial cell lines (HMECs) from breast biopsies of women who showed no LI (N = 6), partial LI (N = 7), or complete LI (N = 6). These cell lines were analyzed for proliferation in culture and profiled for genomic signatures using Affymetrix gene arrays. We also analyzed RNA isolated from a cohort of archived formalin-fixed, paraffin-embedded (FFPE) benign breast biopsy samples from postmenopausal women who had either completed the process of LI (N = 4) or who had not initiated LI (N = 8) for genomic signatures using Whole-Genome DASL Assays. Results: We found that LI was associated with decreased cellular proliferation and inhibition of processes associated with tumor development and progression. Specifically, we found that HMECs derived from benign breast biopsies in which LI was not evident showed increased proliferation and elevated expression of Twist (p = 0.002), a transcription factor associated with epithelial-mesenchymal transition (EMT) and breast cancer development. We are assessing differentially expressed genes for association with breast cancer risk using a nested case:control group of benign breast biopsies from women in our cohort who subsequently developed breast cancer (N = 85) vs those who did not (N = 142) and for whom LI status at the time of initial biopsy was known. Conclusions: LI may decrease cancer risk through inhibition of key tumorigenic processes. Identification of processes associated with the physiologic risk reduction seen with LI may provide insight into novel avenues for risk reduction. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-06-01.