Notch3 as a Tumor Suppressor in the Postpartum Mammary Gland
Abstract
Postpartum breast cancer is an under-recognized and highly metastatic subset of young women?s breast cancer, generally referred to as being diagnosed within 5 years of a women?s most recent childbirth. Epidemiological studies indicate that about 45% of breast cancers in women 45 years of age or younger are diagnosed within 5 to 6 years of their childbirth, highlighting postpartum breast cancer as a significant unmet clinical need. The poor outcomes of postpartum breast cancer do not appear to be associated with pregnancy per se, rather, unique biology of the postpartum breast is implicated in the rapid progression of this disease. In particular, the microenvironment of postlactational involuting breast proves to stimulate tumor growth, local tumor cell dissemination, and distant metastasis. Further understanding of the molecular mechanisms underlying the increased risk for metastasis and death may lead to identification of targeted interventions that will benefit the large number of women with breast cancer who fall into this subset. Recently we discovered that deletion of Notch3, a gene playing an important role in mammary development, induced formation of ER(alpha)-positive metastatic breast cancer, specifically in parous mice. The postpartum mammary glands in these mice displayed an increased inflammatory response associated with downregulation of lipid metabolism; in particular, depletion of brown adipocytes. In addition to the altered microenvironment, these mice showed expansions of mammary progenitor populations. Inappropriate progenitor propagation may lead to tumor initiation, while exacerbated inflammatory microenvironment may accelerate tumor growth and metastasis. Interestingly, high level expressions of Notch3 and genes promoting brown adipocyte differentiation are significantly associated with prolonged survival in subsets of human breast cancer patients. We hypothesize that Notch3 functions as a tumor suppressor in postpartum mammary gland by promoting brown adipocyte differentiation during post-lactational involution, which may ameliorate the pro-tumorigenic inflammatory microenvironment and by restricting mammary stem/progenitor cell proliferation in the postpartum mammary gland. We will test our hypothesis with the following specific aims: (1) determine whether post-lactational involuting mammary microenvironment of Notch3 knockout mice accelerates tumor growth and metastasis compared to that of wildtype mice, and whether Notch3 functions in the mammary epithelium or the stroma in this context; (2) determine how Notch3 regulates brown adipocyte differentiation in the involuting breast, and whether brown adipocytes have an impact on the postpartum mammary microenvironment; (3) determine the regulation of parity-induced mammary epithelial cells or other stem/progenitor populations by Notch3 in the postpartum mammary gland. This project is based on a novel finding of Notch3 being a tumor suppressor in the postpartum mammary gland and a unique parous mouse model that gives rise to ER(alpha)-positive metastatic breast cancer. We will determine the mechanisms underlying brown adipose tissue repopulation in the postpartum mammary gland as well as its potential role in modulating postpartum mammary microenvironment, which may link obesity or obesity-associated metabolic changes to the progression of postpartum breast cancer. We will test whether agents that promote brown adipocyte differentiation decelerate tumor growth and/or metastasis in the postpartum mammary gland, which may lead to development of new interventions for postpartum breast cancer. In addition, we may identify cellular origin of highly metastatic postpartum breast cancer and the signaling dysregulated during initiation of the disease. Taken together, successful completion of this project may lead to identification of genetic risk, understanding of initiation and progression, and ultimately, development of effective diet supplementation or che
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 05, 2019
- Source ID
- W81XWH1910031
Entities
People
- Keli Xu
Organizations
- United States Army
- University of Mississippi Medical Center