The role of breast stem cells in early stages of breast carcinogenesis

About This Grant

Breast tissue is dynamic and undergoes significant structural changes throughout a woman's life. The breast tissue architecture is maintained by a population of stem cells with self-renewal capacity which are essential for tissue repair and remodeling. Recently, the role of stem cells in breast carcinogenesis has been recognized as a high priority for translational breast cancer (BCa) research. The stem cell hypothesis of breast carcinogenesis suggests that breast cancer development might be directly related to the size of the stem cell pool and its mitotic activity. Further, in the mammary gland, stem cells are the only cell subpopulation that has capacity to accumulate all the oncogenic alterations. This project will fill gaps in our understanding of the role of stem cells in the early stages of breast carcinogenesis and their interplay with BCa risk factors by focusing on co-stained stem cell marker combinations that are reflective of high-risk stem cell lineages. Specifically, we will explore: 1) the associations of high-risk stem cell lineages (CD44+/CD24-/low, EpCAM-/low/CD49fhigh and ALDH1A1high/CD44+/CD133+) in histologically normal breast tissue with mammographic percent density and AI- based mammographic features (n=1,290); 2) the associations of high-risk stem cell lineages with subsequent BCa risk in women with a previous benign biopsy (444 cases/1,003 controls); and 3) the associations of hormone-related factors (oral contraceptives, menopausal hormone therapy, alcohol use, body mass index, weight gain since age 18, and reproductive factors) with high-risk stem cell lineages (n=1,834). We will use prospectively collected data/samples/ mammograms from cancer-free women with benign breast disease (BBD) within the Nurses' Health Study (NHS), NHS II, Washington University's Women's Health Repository (WHR), and a unique collection of data/samples/mammograms from healthy women in the Komen Tissue Bank, with the final study population representative of US demographics. Stem cell markers will be stained on study tissue microarrays (specifically constructed from histologically normal breast tissue regions) with commercially available antibodies using multiplex immunofluorescence, and the staining results will be evaluated with automated image analysis. We propose a highly novel investigation that will comprehensively examine the role of stem cell markers in breast carcinogenesis. The study aims to shed light on molecular pathways behind the observed associations of risk factors with BCa risk as well as to identify markers that could advance future risk prediction in a large segment of high-risk women undergoing routine breast biopsies and those with high-risk mammographic features. This proposal could pave the way for novel personalized breast cancer prevention and surveillance strategies. As stem cell activity is potentially modifiable via a variety of targeted therapies, the findings could translate into stem cell -directed pharmaceutical interventions aimed at BCa risk reduction in high-risk women with BBD and/or high mammographic breast density in whom novel prevention strategies are urgently needed.