Possible ErbB-NF-κB pathways in breast cancer stem cells for tumorigenesis

Proceedings of National Academy of Science, USA doi: 10.1073/pnas.111327110

Kunihiko Hinohara1, Seiichiro Kobayashi2, Hajime Kanauchi3, Seiichiro Shimizu4, Kotoe Nishioka5, Ei-ichi Tsuji5, Kei-ichiro Tada5, Kazuo Umezawa6, Masaki Mori7, Toshihisa Ogawa5, Jun-ichiro Inoue8, Arinobu Tojo2 and Noriko Gotoh1

1 Division of Systems Biomedical Technology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639; 2 Division of Molecular Therapy, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639; 3 Department of Breast and Endocrine Surgery, Showa General Hospital, Kodaira-shi, Tokyo 187-8510; 4 Department of Pathological Diagnosis, Showa General Hospital, Kodaira-shi, Tokyo 187-8510; 5 Department of Breast and Endocrine Surgery, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655; 6 Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Yokohama-shi, Kanagawa 223-8522; 7 Department of Gastroenterological Surgery, Osaka University, Suita-shi, Osaka, 565-0871; 8 Division of Cellular and Molecular Biology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639

Cancer stem cells (CSCs), which make up only a small proportion of heterogeneous tumor cells, may possess a greater ability to maintain tumorigenesis than do other tumor cell types. CSCs can self-renew and simultaneously produce differentiated daughter cells; thus they can strongly proliferate until they reach their final differentiated state. Because most cancer cells proliferate extensively, traditional cancer therapies aim to eliminate as many cancer cells as possible by targeting cells with increased proliferation activity. However, relapse occurs in a significant number of patients even after complete tumor resection and systemic treatment involving chemotherapy and/or radiotherapy. This is because CSCs are relatively resistant to conventional chemotherapy and radiotherapy and might survive after systemic treatment. These cells may remain dormant for years but eventually cause relapse. Therefore, cancer therapy should target CSCs that were not targeted by conventional therapy. Although the concept of CSCs greatly influences cancer biology and evokes reconsideration of cancer treatment, the molecular mechanisms underlying the contribution of these cells to tumorigenesis remain obscure. To develop more effective cancer therapies, it is critical to understand the mechanism by which CSCs are maintained in the body.

Here, we discovered possible molecular mechanisms that are critical for maintenance of self-renewing breast CSCs in the body. We showed that Heregulin (HRG), a ligand for ErbB3 receptor tyrosine kinase, is able to maintain mammospheres, in vitro-cultured cell aggregation, that are derived from single cancer stem-like cells in the breast cancer tissues of the patients. Our findings further demonstrate that ErbB-phosphatidyl inositol 3-kinase (PI3K)-NF-kB axis is essential for the HRG-induced mammosphere formation. The HRG-induced activation of NF-kB induces production of proinflammatory cytokines and chemokines, including interleukin-8 (IL-8) for self-renewal of breast CSCs, vascular epidermal growth factor (VEGF) for angiogenesis and CCL5 for immune response. These paracrine factors may actively generate and maintain a microenvironment for the survival and proliferation of breast CSCs, or in other words, a breast CSC niche. It is thus important to target molecules involved in the ErbB-PI3K-NF-kB pathway in order to eradicate breast cancer.

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