Abstract
Pregnancy-associated breast cancer (PABC) is diagnosed during or shortly after pregnancy. Although rare, PABC is a serious occurrence often of the triple negative (TNBC) subtype. Here we show progesterone, prolactin, and RANKL upregulate BRCA1-IRIS (IRIS) in separate and overlapping subpopulations of human mammary epithelial cell lines, which exacerbates the proliferation, survival, and the TNBC-like phenotype in them. Conversely, vitamin D3 reduces IRIS expression in TNBC cell lines, which attenuates growth, survival, and the TNBC-like phenotype in them. In the mouse, Brca1-Iris (Iris, mouse IRIS homolog) is expressed at low-level in nulliparous mice, increases ~10-fold in pregnant/lactating mice, to completely disappear in involuting mice, and reappears at low-level in regressed glands. Mice underwent 3 constitutive pregnancies followed by a forced involution (after 5 days of lactation) contained ~10-fold higher Iris in their mammary glands compared to those underwent physiological involution (after 21 days of lactation). While protein extracts from lactating glands promote proliferation in IRISlow and IRIS overexpressing (IRISOE) cells, extracts from involuting glands promote apoptosis in IRISlow, and aneuploidy in IRISOE cells. In a cohort of breast cancer patients, lack of breastfeeding was associated with formation of chemotherapy resistant, metastatic IRISOE breast cancers. We propose that terminal differentiation triggered by long-term breastfeeding reduces IRIS expression in mammary cells allowing their elimination by the inflammatory microenvironment during physiological involution. No/short-term breastfeeding retains in the mammary gland IRISOE cells that thrive in the inflammatory microenvironment during forced involution to become precursors for aggressive breast cancers shortly after pregnancy.