Involution-based biomarkers of breast cancer risk

Premenopausal parous women are at increased risk of postpartum breast cancer (PPBC), a highly aggressive disease during a period extending up to 5 to 10 years after childbirth, and is characterized by poor prognosis and survival, and a 2-fold increased risk of metastasis. PPBCs account for 35-55% of breast cancers diagnosed among women younger than 45 years of age in United States, and disproportionately affect African American women, thus exacerbating breast cancer disparity. The parent grant related to this supplement seeks to identify involution-based biomarkers of breast cancer risk in postmenopausal women. These are women aged 50 years and older, for whom age-related involution (LI) (regression of breast epithelial tissue with age) should be complete, but our BBD cohort shows that more than 40% of these women have not completed LI, and are at substantially greater risk of developing breast cancer compared to women of similar age whose involution process has completed. The population studied in our parent grant is > 50 years of age; therefore, it cannot adequately investigate biomarkers of postpartum breast cancers, which occur in younger women <45 years. This supplement project seeks to define interferon-associated signaling pathways involved in the development and progression of PPBC, which would lead to more focused surveillance, earlier detection, and development of preventative strategies to reduce PPBC and breast cancer disparity. We previously showed that interferoninduced transmembrane protein 1 (IFITM1), an interferon stimulated gene (ISG), was critical for tumorigenic characteristics in breast cancer cells. We have now obtained preliminary data from a targeted set of young women (age <45) which showed that the ISGs IFITM1 and STAT1, and the interferon receptor IFNAR1, were elevated in parous women. We hypothesize that activation of these genes in postpartum mammary tissue due to dysregulated interferon signaling, may lead to increased epithelial cell proliferation, decreased apoptosis, and increased susceptibility to tumor development in the postpartum period. We aim to define the ISGs associated with tumor-promoting pathways, and PPBC risk markers in women with benign breast disease (BBD). To achieve these aims, we will use human mammary epithelial cells (HMEC) derived from patient breast tissues in our recently developed organoid biobank, and breast tissue biopsies from the Mayo BBD cohort. We will use HMEC lines to assess tumorigenic processes and expression of ISGs in parous and nulliparous women, and tissues from the Mayo BBD cohort to assess expression of ISGs by immunohistochemistry in a set of parous BBD patients who developed breast cancer within 10 years of a last birth (cases) matched on patient age, biopsy date, and followup period with women who did not (controls). The successful completion of this project would lead to identification of ISG biomarkers of PPBC, improved breast cancer risk prediction, reduced disparities in breast cancer, and establishment of Dr. Ogony as an independent investigator.