Date of Award
breast cancer, cell cycle regulation, resistance
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This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
Classification of breast cancer relies on the presence or absence of estrogen receptor alpha (ERα) and progesterone receptor (PR) as well as the overexpression or amplification of the Her2/neu receptor. Targeted therapies against these proteins has increased the overall 5-year survival rate of breast cancer patients. However, a subset of breast cancer patients can acquire resistance or are initially unresponsive to these therapies. Understanding the molecular pathways that can cause resistance within the various types of breast cancer is of high priority. The cell cycle regulatory factor Speedy (Spy1) has been found to be upregulated in a variety of human cancers, including invasive mammary carcinomas, as well as being downstream of two important pathways in breast cancer initiation and progression; MAPK and c-Myc. My study sought to investigate the role of Spy1 downstream of ERα and to determine its role in regulating treatment response in the presence or absence of ERα. My work defines a novel positive feedback loop whereby Spy1 activates ERK1/2 in a MEK-independent fashion. This activation was further demonstrated to increase the ligand-independent activation of ERα, correlating with a decrease in tamoxifen sensitivity. We tested our findings using an in vivo zebrafish model, demonstrating elevated levels of Spy1 alter tamoxifen sensitivity. We further demonstrate significantly high levels of Spy1 within the triple negative group of breast cancers; which correlates with decreased sensitivity to chemotherapy as well as CDK inhibitor treatment. These data could define an efficient mechanism driving proliferation and resistance in select cancers and may represent a potent drugable target.
Ferraiuolo, Rosa-Maria, "Novel Cell Cycle Regulation in Breast Cancer Treatment Resistance" (2015). Electronic Theses and Dissertations. 5431.