Abstract
Abstract : The overall purpose of this project is to investigate the role of HOXC10 in breast cancer tumorigenicity and drug resistance. Since it was previously shown to be involved in proliferation and cell cycle, we investigated at the molecular level the role of HOXC10 and found that by affecting the RB/E2F1 pathway, it controls proliferation, G1/S transition and new origin firing. On the other hand, HOXC10 activates NF-kb, G2/M checkpoint and DNA repair through NER pathway, protecting cells from apoptosis and DNA damage, especially DNA crosslinks. This eventually leads the cells to become less sensitive to chemotherapy treatment. Mechanistically, HOXC10 binds to CDK7 and stimulates its kinase activity towards RNA polymerase II after DNA damage, allowing the cells to finish their repair and to recover from DNA damage arrest by restarting their transcription and protection from apoptosis. Consequently, inhibiting CDK7 could restore chemosusceptibility. Finally, high HOXC10 expression is correlated with poor outcome and with chemoresistance in breast cancer patients and cell lines.
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