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THE CONTRIBUTION OF K+ ION CHANNELS AND THE Ca2+-PERMEABLE TRPM8 CHANNEL TO BREAST CANCER CELL PROLIFERATION.

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dc.contributor.author Roy, Jeremy
dc.date.accessioned 2010-11-24T18:43:33Z
dc.date.available 2010-11-24T18:43:33Z
dc.date.issued 2010-11-24
dc.identifier.uri http://hdl.handle.net/10222/13118
dc.description.abstract Breast cancer is the most prevalent cancer type among Canadian women. Breast cancers originate from the malignant transformation of mammary epithelial cells, which causes them to adopt an uncontrolled cell proliferation phenotype. My research suggests that the activity of specific ion channels (KV10.1, KCa3.1 and TRPM8) contribute to the proliferation of MCF-7 cells, a cell line commonly used to study breast cancer in vitro. Pharmacologically inhibiting the activities of KV10.1 or KCa3.1 channels decreased basal, but not estrogen-stimulated [3H]-thymidine incorporation, demonstrating that these channels contribute to MCF-7 cell proliferation. One way K+ channel activity is hypothesized to control cell proliferation is via regulation of membrane potential-dependent Ca2+ influx. Inhibition of KCa3.1 but not KV10.1 channel activity resulted in a membrane potential-dependent decrease in basal Ca2+ influx, suggesting that the way in which KCa3.1 channels contribute to cell proliferation is via regulating Ca2+ influx. In addition, my research also demonstrated that TRAM-34 increased or decreased cell proliferation depending on the concentration used and mitogenesis by TRAM-34 was blocked by estrogen receptor antagonists. TRAM-34 increased progesterone receptor mRNA expression, decreased estrogen receptor-alpha mRNA expression and reduced the binding of radiolabelled estrogen to estrogen receptor protein, in each case mimicking the effects of estrogen. Our finding that TRAM-34 is able to activate the estrogen receptor suggests a novel action of this supposedly specific K+ channel inhibitor and raises concerns of interpretation in its use. TRPM8 channels were also identified in MCF-7 cells, where they appeared to be important Ca2+ entry pathways. Inhibiting the activity of TRPM8 pharmacologically, as well as knocking down TRPM8 mRNA expression decreased cell proliferation, indicating that TRPM8 also contributed to MCF-7 cell proliferation. In conclusion, my research demonstrates that the activities of KV10.1, KCa3.1 and TRPM8 channels contribute to basal breast cancer cell proliferation. These findings suggest that the activity of specific ion channels may be potential targets for future therapeutic agents to treat breast cancer. en_US
dc.language.iso en en_US
dc.subject Cancer, Ion channels, Breast Cancer, Potassium Channels, Calcium Channels, Cell Proliferation, TRPM8 en_US
dc.title THE CONTRIBUTION OF K+ ION CHANNELS AND THE Ca2+-PERMEABLE TRPM8 CHANNEL TO BREAST CANCER CELL PROLIFERATION. en_US
dc.date.defence 2010-10-26
dc.contributor.department Department of Physiology & Biophysics en_US
dc.contributor.degree Doctor of Philosophy en_US
dc.contributor.external-examiner Ryszard Grygorczyk en_US
dc.contributor.graduate-coordinator Elizabeth Cowley en_US
dc.contributor.thesis-reader Elizabeth Cowley en_US
dc.contributor.thesis-reader Eileen Denovan-Wright en_US
dc.contributor.thesis-reader Younes Anini en_US
dc.contributor.thesis-supervisor Paul Linsdell en_US
dc.contributor.ethics-approval Not Applicable en_US
dc.contributor.manuscripts Not Applicable en_US
dc.contributor.copyright-release Not Applicable en_US


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