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dc.contributor.advisorLyons, Traci R.
dc.contributor.authorTarullo, Sarah Elizabeth
dc.contributor.committeememberPrekeris, Rytis
dc.contributor.committeememberSartorius, Carol
dc.contributor.committeememberKabos, Peter
dc.contributor.committeememberGutierrez-Hartmann, Arthur
dc.contributor.committeememberHansen, Kirk
dc.contributor.committeememberBorges, Virginia
dc.date.accessioned2020-01-14T15:44:31Z
dc.date.available2022-01-06T15:44:31Z
dc.date.submitted2019
dc.descriptionIncludes bibliographical references.
dc.descriptionFall
dc.description.abstractBreast cancer (BC) remains the second leading cause of cancer-related deaths for women in the US—mainly due to metastatic disease. Additionally, women aged <45 who are within 5-10 years of most recent childbirth at BC diagnosis are ~3 times more likely to develop metastasis and die from BC than age- and stage-matched nulliparous patients. We define these cases as postpartum BC (PPBC) and propose that the unique biology of the postpartum mammary gland drives tumor progression. Our published results revealed roles for Semaphorin 7a (SEMA7A), an axon guidance protein, in breast tumor cell growth, motility, invasion, and tumor associated-lymphangiogenesis, all of which are also increased in pre-clinical models of PPBC. However, whether SEMA7A drives progression in PPBC remains largely unexplored. As described in Chapter III, using a preclinical model of PPBC we show that silencing of SEMA7A decreases postpartum induced tumor growth and invasion, while overexpression is sufficient to induce increases in growth and invasion in nulliparous hosts. Further, we show SEMA7A promotes tumor-associated COX-2 expression, fibroblast-mediated collagen deposition in the tumor microenvironment, and tumor-associated fibronectin (FN) deposition to promote tumor cell survival via activation of AKT. We further demonstrate a role for SEMA7A in the development of distant metastasis and show that co-expression of SEMA7A/COX-2/FN predicts for poor prognosis in BC patients. These studies suggest SEMA7A as a key mediator of BC progression and that targeting SEMA7A may open avenues for novel therapeutic strategies. In Chapter IV, I explore therapeutic vulnerabilities of SEMA7A-mediated BC progression. Using investigative targeted therapies, we demonstrate that targeting ERK decreases cell proliferation, clonogenicity, and invasion in 3D in SEMA7A-overexpressing BC cells. Furthermore, our analysis of RNA sequencing data comparing high and low SEMA7A expressing BC cells reveals SEMA7A expression alters numerous signaling pathways. Additionally, we provide evidence that direct targeting of SEMA7A has the potential to reduce cell viability. Finally, I discuss my experiences with Dr. Virginia Borges in the Breast Clinic and the potential for using SEMA7A as a biomarker in BC patients. Overall, these studies suggest multifaceted roles for SEMA7A in BC progression and have the potential to open novel therapeutic strategies to improve the survival of BC patients.
dc.identifierTarullo_ucdenveramc_1639D_10696.pdf
dc.identifier.urihttps://hdl.handle.net/10968/4777
dc.languageEnglish
dc.publisherUniversity of Colorado at Denver, Anschutz Medical Campus. Health Sciences Library
dc.rightsCopyright of the original work is retained by the author.
dc.rights.accessEmbargo Expires: 01/06/2022
dc.subjectsemaphorin 7a
dc.subjectpostpartum breast cancer
dc.subject.meshCyclooxygenase 2
dc.subject.meshSemaphorins
dc.subject.meshBreast Neoplasms
dc.subject.meshNeoplasm Invasiveness
dc.titleSemaphorin 7A drives breast cancer progression through intrinsic and extrinsic mechanisms
dc.typeThesis
dcterms.embargo.expires2022-01-06
thesis.degree.disciplineCancer Biology
thesis.degree.grantorUniversity of Colorado at Denver, Anschutz Medical Campus
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy (Ph.D.)


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