Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Physiology and Pharmacology

Supervisor

Dr. Dale W. Laird

Abstract

The identification of key regulators of breast cancer onset and progression is critical for the development of targeted therapies. Connexins and pannexins are characterized by their ability to form large-pore channels and are frequently dysregulated in cancer. However, their role in breast cancer progression remains poorly understood due to a lack of in vivo models capable of assessing the proposed and opposing roles of connexins and pannexins as both tumor suppressors and/or facilitators in multiple stages of the disease. Using 2 previously uncharacterized genetically-modified mice, connexin43 (Cx43) and connexin26 (Cx26) were evaluated for their role in normal mammary gland development and function prior to using the mice to assess their linkage to breast cancer onset and progression. In addition, pannexin1 (Panx1) was evaluated for the first time in the context of mammary gland development and correlated to clinical outcomes in patients with breast cancer using in silico arrays. Using a mouse model expressing a loss-of-function Cx43 mutant it was revealed that the severity of milk ejection defects associated with Cx43 are linked to its functional status. Using a similar mouse model induced to develop primary breast cancer lesions, we identified that low functional levels of Cx43 resulted in mainly hyperplasic mammary glands that greatly increased the frequency of developing metastases to the lungs. Our assessment of mice with conditional knockdown of Cx26 during pregnancy revealed that basal levels of Cx26 were sufficient for normal alveolar development and proper lactation, but increased the susceptibility of mammary tumor onset in a chemically induced mouse model of breast cancer. Finally, genetically modified mice with systemic knockout of Panx1 identified a role for Panx1 in timely alveolar development during early lactation. In addition, Panx1 mRNA expression was correlated with worse clinical outcomes in breast cancer. Collectively, our results redefine our view of Cx43, Cx26 and Panx1 in mammary gland development; supporting a tumor suppressive role for Cx43 and Cx26, and a tumor facilitating role for Panx1 in breast cancer progression which may have implications for extending to their use as therapeutic targets.


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