Identifying cells-of-origin for cancer and understanding the mechanisms governing expansion of these cells (referred to as tumor-initiating cells (TICs) here) are of great importance for early prevention, detection and formulating novel therapeutic strategies. In the normal mammary gland, basal epithelial cells contain mammary stem cells which are able to self-renew and differentiate into all lineages of breast epithelium. Longevity of these tissue stem cells and their slow proliferating potential make them good targets for accumulating oncogenic events. Our earlier studies revealed that ErbB2-induced mammary tumors originate primarily from basal mammary epithelial cells (referred to as basal TICs) and to a much lesser extent from luminal progenitors (referred to as luminal TICs). We further identified that the NF-κB-inducing kinase/IκB kinase α (NIK/IKKα) module is critical for maintaining basal TICs, but not luminal TICs, primarily by phosphorylating Kip1/p27 and leading to its cytoplasmic re-localization. Our interest is to examine the effect of different tumor TICs on mammary tumor progression, metastasis and drug resistance and to determine if targeting the NIK/IKKα module and its related components will synergize with anti-ERBB2 therapy.

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Weizhou Zhang, Wei Tan, Xuefeng Wu, Maxim Poustovoitov, Amy Strasner, Wei Li, Nicholas Borcherding, Majid Ghassemian, and Michael Karin A NIK-IKKα module expands ErbB2-induced tumor- initiating cells by stimulating nuclear export of p27/Kip1. 2013. Cancer Cell. In press.