Postpartum breast cancer, defined as the diagnosis of breast cancer within 5 years of pregnancy, has a 3-fold increased risk for distant recurrence and mortality. A postpartum diagnosis is an independent risk factor for poor prognosis, isolating the postpartum window from potential tumor promotional attributes of pregnancy. The postpartum mammary gland undergoes involution to return the lactation-competent gland to a non-secretory state. In rodent models, postpartum involution is tumor-promotional due to tissue remodeling and macrophage infiltration. Unknown is whether the postpartum period also exhibits stromal remodeling at secondary sites, which could increase metastasis. The question of whether normal physiologic tissue remodeling occurs in organs besides the mammary gland in the postpartum period, and escalates breast cancer metastasis, has not been previously explored. My novel observation that macrophages infiltrate the postpartum liver, reminiscent of mammary gland involution, suggests that postpartum liver tissue remodeling establishes a pro-metastatic microenvironment during weaning-induced involution. The hypothesis that macrophage infiltration in the postpartum liver establishes a pro-metastatic microenvironment that supports breast cancer metastasis;and further, that prophylactic treatment with NSAIDs reduces the pro-metastatic attributes of the regressing liver as well as liver metastases, will be tested.
Aim 1 will determine the extent of macrophage infiltration into the liver during involution including a characterization of the pro-tumor immunosuppressive differences of macrophages in the postpartum liver compared to nulliparous controls. The contribution of infiltrating macrophages to liver involution and the postpartum pro-metastatic microenvironment will be evaluated using a conditional macrophage-depletion mouse model.
Aim 2 a will test if mammary tumor cell metastasis is increased in the postpartum period using murine models of metastatic postpartum breast cancer.
Aim 2 b will test if liver metastasis is increased in University of Colorado postpartum breast cancer patients when compared to their nulliparous breast cancer peers.
Aim 3 will determine if treatment with NSAIDs in our murine model of postpartum breast cancer decreases the pro-metastatic attributes of the postpartum liver and reduces liver metastasis. This work will further contribute to our understanding of the postpartum period as a window of risk for metastatic breast cancer by investigating the role of the liver pro-metastatic microenvironment. The proposal aims to identify novel treatment options for young women at risk for postpartum breast cancer. The project's progression will be frequently assessed by the Schedin lab research team and collaborators with complimentary expertise in basic science and clinical fields. To accomplish these aims, proficiency in flow cytometric, histologic, ¯ophage functional assays, use of transgenic, metastasis, and treatment murine models, as well as human clinical databases will advance the student's scientific breadth to better understand human postpartum breast cancer.

Public Health Relevance

Women diagnosed with breast cancer within 5 years of a pregnancy, termed postpartum breast cancer, have a greater risk of dying from the disease compared to their never-been-pregnant peers or peers further than 5 years out from their last pregnancy. This proposal aims to understand if stromal remodeling in the liver during the postpartum timeframe increases the risk of breast cancer spread to the liver, in a deadly process known as metastasis. This work will also investigate the use of readily available Non-Steroidal Anti-Inflammatory Drugs as a potential method of preventing metastasis of postpartum breast cancers to the liver.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Schmidt, Michael K
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Oregon Health and Science University
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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 :