Author

Erica Goddard

Date

1-2017

Document Type

Dissertation

Degree Name

Ph.D.

Department

Cancer Biology

Abstract

A postpartum breast cancer diagnosis, defined as a diagnosis within 5 years of a pregnancy, is an independent risk factor for metastasis and death compared to breast cancers diagnosed in nulliparous or pregnant patients. The work described here investigates potential mechanisms unique to the postpartum woman that might be responsible for increased metastasis. Metastatic success requires tumor cells to successfully navigate the metastatic cascade, including immune escape, local dissemination, intravasation/entry into vasculature, survival in the circulation, extravasation/exit from vasculature, and finally seeding, survival, and outgrowth at secondary sites. Work by the Schedin lab has identified post-weaning mammary gland involution, physiologic tissue regression characterized by ECM remodeling and immune influx, as a major contributing factor to the increased risk for metastasis observed in postpartum breast cancers. Specifically, mammary gland involution promotes early steps of the metastatic cascade including primary tumor growth, immune escape, local dissemination, and increased intravasation. However, later events in the metastatic cascade, particularly survival and outgrowth at the secondary site, represent major bottlenecks to metastatic efficiency. One identified way of overcoming these bottlenecks is establishment of tumor-educated pro-metastatic niches, defined as secondary microenvironments supportive of tumor cell seeding and outgrowth. I hypothesized that secondary sites are altered post-weaning, establishing pro-metastatic niches in the absence of tumor education, such that tumor cell seeding and/or outgrowth are promoted specifically in postpartum breast cancers. This dissertation describes the discovery of weaning-induced liver involution, a tissue-remodeling event that establishes a transient pro-metastatic microenvironment that is more supportive of disseminated tumor cell seeding and/or survival. These studies predict elevated site-specific liver metastasis in postpartum breast cancers. Importantly, I observed elevated risk for liver metastasis, but not lung, bone, or brain metastasis, in rodent models of postpartum breast cancer, and in postpartum breast cancer patients, suggesting a postpartum phenomenon unique to the liver. Additionally, non-steroidal anti-inflammatory drugs (NSAIDs) that target cyclooxygenases (Cox-1/Cox-2) have shown efficacy in abrogating early events in the metastatic cascade in preclinical models. I explored NSAIDs as an avenue of reducing liver metastasis in the postpartum setting in rodents. Data from these NSAID studies suggest that low-dose ibuprofen has effects on the liver microenvironment distinct from those in the mammary gland, but does not abrogate the increased risk for postpartum liver metastasis. Finally, to better understand the high risk for metastasis associated with postpartum breast cancer diagnoses, I have participated in a retrospective study in young women with breast cancer (n=804). This work revealed that postpartum breast cancers, particularly those diagnosed at stage II, are more likely to present with lymph node metastasis and develop distant metastasis despite similar tumor size at diagnosis. In this cohort, I have also identified that postpartum breast cancer patients with estrogen receptor negative disease represent a breast cancer subset at particularly high risk for metastasis. In sum, this dissertation describes an essential role for the transient pro-metastatic microenvironment established in the post-weaning liver in facilitating postpartum breast cancer metastasis and provides new insight into the high risk for metastasis in postpartum breast cancers.

Identifier

doi:10.6083/M40K27NV

School

School of Medicine

Available for download on Thursday, February 06, 2020

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