Related to research question above, we will also explore molecules and pathways differentially involved in basal or luminal TIC-formed tumors. We hope to identify targets other than NIK/IKKα module for both basal and luminal TIC-formed tumors. NIK/IKKα module has been proved to be hard druggable targets due to the following reasons: 1. Full length of NIK protein cannot be purified for large chemical library screening; 2. IKKα is homologous to IKKβ, which makes it hard to find specific inhibitors for IKKα. IKKβ inhibition causes critical immunological complications rendering patients higher tendency for infection. Although our mouse study indicates basal TIC are the major TIC for ErbB2-induced tumorigenesis, it is still questionable if human ERBB2+ breast cancer follows the same scheme. Thus identification of pathways important for expansion of both basal and luminal TICs may provide a rationale for combinatory therapy to efficiently prevent and treat ERRB2+ breast cancer. We are trying to identify signaling pathways that are important for both basal and luminal TIC formed tumors using a combination of transcriptome analysis, biochemical methods, and mouse models.

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Michael Karin. The IkappaB kinase - a bridge between inflammation and cancer. 2008. Cell research. 18(3): 334-42

Weizhou Zhang, Wei Tan, Xuefeng Wu, Maxim Poustovoitov, Amy Strasner, Wei Li, Majid Ghassemian, Andrew Koff, and Michael Karin. A NIK-IKKα module promotes ErbB2-induced mammary tumorigenesis and tumor initiating cell expansion by stimulating nuclear export of tumor suppressor p27/Kip1. 2013. Cancer Cell. In press.