While previously unrecognized, it is now documented that having delivered a child within 10 years is an independent predictor of early onset breast cancer and poor outcomes. These cancers, based largely on work from our labs, is now referred to as postpartum breast cancer (PPBC), and represents a significant clinical problem. Every year in the US alone, ~15,000 young women (accounting for ~50% of all young women?s breast cancer cases) are diagnosed during the high risk, postpartum period. Research in our lab has advanced the hypothesis that weaning-induced mammary gland involution is the driver of increased incidence and metastasis in PPBC patients. During the transitory window of weaning-induced involution, the normal involuting mammary gland is skewed towards a pro-tumor microenvironment, as it exhibits increased lymphangiogenesis, fibroblast activation, and extracellular matrix deposition; as well as enrichment for myeloid derived suppressor cells (MDSC), M2-skewed macrophages, and Th-17, Th-2 and Treg skewed T cells compared to nulliparous glands. These discoveries support our hypothesis that sub-clinical, non-life threatening disease progresses to overtly invasive cancer during weaning-induced involution. In multiple murine models, we confirm that the tissue microenvironment of the involuting gland increases mammary tumor incidence and progression. Further, we demonstrate that ibuprofen (IBU) treatment targeted to the involution window blocks >50% of these tumors from emerging, depending on model. Further, of those tumors that do emerge, progression to metastatic disease is suppressed. One mechanism by which IBU appears to inhibit PPBC is through anti-tumor immunity, as IBU increases the number of cytotoxic T cells, consistent with increased immune surveillance. Importantly, we find the ability of IBU to restore the adaptive arm of the immune system occurs in the absence of adverse host autoimmune reactions and does not impact the ability of dams to successfully nurse their young in subsequent pregnancies. These findings support clinical utility of IBU in the setting of a PPBC prevention trial. Our studies also identify opportunities to improve efficacy, and vitamin D (Vit D) is proposed based on its anti-tumor and anti-inflammatory activity, and its safety and particular relevance in postpartum women, who are at high risk for VitD deficiency. Here we propose to 1) investigate the efficacy of IBU treatment in combination with vitamin D, in rodent models of PPBC with improved human relevance, 2) identify the mechanism by which IBU +/- VitD mitigates the pro-tumorigenic microenvironment of the involuting gland with the goal of identifying additional involution-specific targets; and 3) translate our rodent studies defining the ?immune composition of the ?at risk? involuting mammary gland to women, by defining the immune milieu in the normal human breast across reproductive states. Only through understanding how the normal, involuting human breast confers increased BrCa risk, can we identify additional targets to improve the efficacy of our chemoprevention strategy and lay the foundation for PPBC prevention.

Public Health Relevance

Young women?s breast cancer is a particularly deadly disease, and biology related to weaning is the likely cause. With weaning, changes occur in the breast that are very similar to a healing wound and cause increased incidence of metastatic breast cancer in rodent models. The purpose of this research is to test the ability of ibuprofen and vitamin D to prevent these deadly postpartum breast cancers, using relevant rodent models and a unique collection of normal human breast tissue obtained from women during the lactation/weaning cycle.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA169175-07A1
Application #
9993102
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Heckman-Stoddard, Brandy
Project Start
2013-04-01
Project End
2025-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
7
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Elder, Alan M; Tamburini, Beth A J; Crump, Lyndsey S et al. (2018) Semaphorin 7A Promotes Macrophage-Mediated Lymphatic Remodeling during Postpartum Mammary Gland Involution and in Breast Cancer. Cancer Res 78:6473-6485
Minnier, Jessica; Pennock, Nathan D; Guo, Qiuchen et al. (2018) RNA-Seq and Expression Arrays: Selection Guidelines for Genome-Wide Expression Profiling. Methods Mol Biol 1783:7-33
Pennock, Nathan D; Martinson, Holly A; Guo, Qiuchen et al. (2018) Ibuprofen supports macrophage differentiation, T cell recruitment, and tumor suppression in a model of postpartum breast cancer. J Immunother Cancer 6:98
Betts, Courtney B; Pennock, Nathan D; Caruso, Breanna P et al. (2018) Mucosal Immunity in the Female Murine Mammary Gland. J Immunol 201:734-746
Bruno, Robert D; Fleming, Jodie M; George, Andrea L et al. (2017) Mammary extracellular matrix directs differentiation of testicular and embryonic stem cells to form functional mammary glands in vivo. Sci Rep 7:40196
Guo, Qiuchen; Betts, Courtney; Pennock, Nathan et al. (2017) Mammary Gland Involution Provides a Unique Model to Study the TGF-? Cancer Paradox. J Clin Med 6:
Goddard, Erica T; Hill, Ryan C; Nemkov, Travis et al. (2017) The Rodent Liver Undergoes Weaning-Induced Involution and Supports Breast Cancer Metastasis. Cancer Discov 7:177-187
Goddard, Erica T; Hill, Ryan C; Barrett, Alexander et al. (2016) Quantitative extracellular matrix proteomics to study mammary and liver tissue microenvironments. Int J Biochem Cell Biol 81:223-232
Goddard, Erica T; Fischer, Jacob; Schedin, Pepper (2016) A Portal Vein Injection Model to Study Liver Metastasis of Breast Cancer. J Vis Exp :
Esbona, Karla; Inman, David; Saha, Sandeep et al. (2016) COX-2 modulates mammary tumor progression in response to collagen density. Breast Cancer Res 18:35

Showing the most recent 10 out of 21 publications