The Role of Prolactin in the Cellular Response to DNA Damaging Agents
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AbstractHigh serum levels of the peptide hormone prolactin are associated with increased breast cancer risk and poor prognosis. Prolactin is also involved in breast cancer resistance to different chemotherapeutics. The overall goal of this project is to investigate potential pathways involved in prolactin induced resistance to DNA damaging agents with the hypothesis that the cross-talk between the prolactin pathway and the DNA damage response is important in the mechanism. We previously identified that one isoform of heat shock protein-90 (HSP90), Hsp90alpha, is a prolactin-Janus kinase-2 (Jak2)-signal transducer and activator of transcription-5 (Stat5) regulated gene in breast cancer cells. We have now observed that prolactin increased the viability of breast cancer cells to DNA damaging chemotherapeutics, and Hsp90 inhibitors, 17AAG and BIIB021, abrogated the effect of prolactin, indicating the mechanism of enhanced viability involves the master cancer chaperone Hsp90. The stability of Jak2 and both the total ataxia-telangiectasia mutated protein (ATM) and phospho-ATM appear to be dependent on functional Hsp90. Inhibition of Jak2 and ATM, with highly selective inhibitors (G6 and KU55933, respectively), abrogated prolactin enhanced viability, suggesting their role in prolactin induced cell viability. Drug combination experiments with Hsp90 inhibitor BIIB021 and doxorubicin, and ATM inhibitor KU55933 and doxorubicin, showed drug synergism between doxorubicin and both KU55933 and BIIB021 in MCF7 breast cancer cells. Interestingly, in orthotopic xenograft studies, autocrine prolactin from human breast cancer cells increased the tumor latency of doxorubicin induced DNA damaged cells in SCID mice compared to untreated or prolactin or doxorubicin alone. We hypothesize that this is in part due to the cross-talk of the prolactin and DNA damage response pathways that may be affecting the tumor microenvironment.
CitationKarayazi Atici, O. (2015). The Role of Prolactin in the Cellular Response to DNA Damaging Agents (Unpublished doctoral thesis). University of Calgary, Calgary, AB. doi:10.11575/PRISM/28347
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