Date of Award

2010

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Molecular and Cellular Biochemistry Program

Abstract

Breast and cervical cancer are two common cancers that severely endanger women's health. The fatality rates of breast and cervical cancer are ranked first and fifth, respectively, in cancer related deaths in women worldwide. Continuous dedication to cancer research is urgently required to elucidate the cancer cell survival mechanism that is responsible for disease aggressiveness and poor prognosis.

Emerging data indicate that Notch-1 is aberrantly regulated in human cervical and ER- breast cancer and inhibiting Notch-1 sensitizes cancer cells to apoptosis. However, the mechanism by which Notch-1 promotes cell survival is not known. NF-КB is also deregulated in these two cancers and might be the downstream signaling effector of Notch-1 to modulate cell survival and apoptosis. Here, we show that Notch-1 may provide cells with survival signal by activating NF-КB activity in cervical and ER- breast cancer.

First, we showed that Notch-1 activates and is required to maintain NF-КB activity in cervical cancer CaSki cells and ER- breast cancer MDA-MB-231 cells. Then, we found that Notch-1 activates NF-КB activity by interacting with IKKα/β and regulating IKKα/β kinase activity in CaSki cells stimulated with TNF-α.

Lastly, we demonstrated that Notch-1 activates NF-КB dependent gene expression in MDA-MB-231 cells through an Akt/IKK dependent pathway. We showed that Notch-1

and IKKα are required for the expression of a subset of NF-КB dependent genes. Notch activation mediated by Jagged-1 or EDTA activates Akt, which in turn activates the IKK complex. Notch activation mediated by Jagged-1 also induces NF-КB subunits, Pol II and IKKα recruitment to the NF-КB dependent gene promoters. Inhibiting Akt pharmacologically or genetically reduces the IKK activation and decreases NF-КB subunits, Pol II and IKKα recruitment to the NF-КB dependent gene promoters.

In summary, we showed that Notch-1 activates NF-КB activity in both cervical and ER- breast cancer cells, and we explored similarities and differences in the underlying mechanisms in the two cell types. Potentially, this study will provide a molecular rationale for targeting Notch-1, Akt and NF-КB in cervical and ER- breast cancer in the clinic.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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Oncology Commons

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