Yi Li, Ph.D.
Department of Molecular and Cellular Biology (Lester and Sue Smith Breast Center)
Ph.D.: Michigan State University, East Lansing
Postdoctoral training: Michigan State University, East Lansing
National Cancer Institute, Bethesda
Memorial Sloan-Kettering Cancer Center, New York
Stem Cells, Wnt, and Breast Cancer
The breast develops from stem cells capable of both self-renewal and differentiation into progenitor cells, which can proliferate many times and progressively differentiate into fully differentiated cells which make up the bulk of the tissue. In mammary ducts, where breast cancers arise, ductal epithelial cells, alveolar epithelial cells, and myoepithelial cells are the principal differentiated cell types. In order to effectively prevent breast cancer initiation and to attack individual breast cancers that do form, we have to understand the interplay of specific oncogenic alterations with specific subsets of breast cells, including stem cells, and to identify oncogenic networks that are crucial in the progression to a transformed state.
This knowledge can only be acquired through prospectively introducing selected oncogenic mutations into different subsets of breast cells (stem cells, progenitor cells, and more differentiated ductal and alveolar epithelial cells), investigating the cellular response in each subset, and discovering what additional oncogenic pathways have to be perturbed in order to achieve the eventual malignant phenotype. And all of these need to occur in the context of normal breast epithelium and stroma. It is impossible to directly seek answers to these questions in healthy women. Cultured cells, xenografts, or even current mouse models are inadequate for addressing these issues. Thus, the initial step of breast carcinogenesis remains largely a mystery, even though it could be a key target for early prevention.
We have developed novel gene transfer methods, based on the TVA retroviral gene delivery technology (clink on the link below to learn more about this technology and the research in the Li lab), to introduce genetic mutations into selected mammary cells in mice at selected times. We are using this method to study how specific subsets of breast cells respond to initiating oncogenes and eventually evolve into cancer, whether the stem cells are especially susceptible, how oncogenic pathways--especially, the Wnt and HER2/Neu signaling pathways--transform breast cells in vivo.
Finally, reproductive history is one of the strongest risk factors for breast cancer - women with a full-term pregnancy at an early age have a 50% reduction in life-time risk of breast cancer compared with women who experience pregnancy late or not at all. However, the mechanism for this protection is not understood, partly because it has been difficult to use animal models to study which oncogenic events pregnancy protects against, and which cell types are protected. The TVA technology now allows us to approach these questions effectively.
- Orsulic, S., Li, Y., Soslow, R.A., Vitale-Cross, L.A., Gutkind, J.S. & Varmus, H.E. Induction of ovarian cancer by defined multiple genetic changes in a mouse model system. Cancer Cell 1, 53-62 (2002). PMID: 12086888.
- Li, Y., Welm, B., Podsypanina, K., Huang, S., Chamorro, M., Zhang, X., Rowlands, T., Egeblad, M., Cowin, P., Werb, Z., Tan, L.K., Rosen, J.M. & Varmus, H.E. Evidence that transgenes encoding components of the Wnt signaling pathway preferentially induce mammary cancers from progenitor cells. Proc Natl Acad Sci U S A 100, 15853-15858 (2003). PMID: 14668450.
- Zhang, X., Podsypanina, K., Huang, S., Mohsin, S.K., Chamness, G.C., Hatsell, S., Cowin, P., Schiff, R. & Li, Y. Estrogen receptor positivity in mammary tumors of Wnt-1 transgenic mice is influenced by collaborating oncogenic mutations. Oncogene 24, 4220-4231 (2005). PMID: 15824740.
- Du, Z., Podsypanina, K., Huang, H., McGrath, A., Toneff, M.J., Bogoslovskaia, E., Zhang, X., Moraes, R.C., Fluck, M.M., Allred, D.C., Lewis, M.T., Varmus, H.E. & Li, Y. Introduction of oncogenes into mammary glands in vivo with an avian retroviral vector initiates and promotes carcinogenesis in mouse models. Proc Natl Acad Sci U S A 103, 17396-17401 (2006). PMID: 17090666.
- Siwko, S., Dong, J., Lewis, M.T., Liu, H., Hilsenbeck, S.G., & Li, Y. Evidence that an early pregnancy causes a persistent decrease in the number of functional mammary epithelial stem cells—implications for pregnancy-induced protection against breast cancer (Cover). Stem Cells 26:3205-9 (2008). PMID: 18787212.
- Reddy, J.P., Peddibhotla, S., Bu, W., Zhao, J., Haricharan, S., Du, Y.C., Podsypanina, K., Rosen, J.M., Donehower, L.A. & Li, Y. Defining the ATM-mediated barrier to tumorigenesis in somatic mammary cells following ErbB2 activation. Proc Natl Acad Sci U S A. 107(8):3728-33 (2010). PMID: 20133707.
- Dong, J., Tong, T., Reynado, A.M., Rosen, J.M., Huang, S. & Li, Y. Genetic manipulation of individual somatic mammary cells in vivo reveals a master role of STAT5a in inducing alveolar fate commitment and lactogenesis even in the absence of ovarian hormones. Dev Biol 345: 196-203 (2010). PMID: 20691178.
- T. Lin, L. Meng, Li, Y. and R. Y.L. Tsai. The Tumor-Initiating Function of Nucleostemin-Enriched Mammary Tumor Cells. Cancer Research. 70:9444-52. (2010). PMID: 21045149.
- Bu, W., Chen, J., Morrison, G.D., Huang, S., Creighton, C.J., Huang, J., Chamness, G.C., Hilsenbeck, S.G., Roop, D.R., Leavitt, A.D. & Li, Y. Keratin 6a marks mammary bipotential progenitor cells that can give rise to a unique tumor model resembling human normal-like breast cancer. Oncogene 30, 4399-4409 (2011). PMID: 21532625.
- Dong, J., Huang, S., Caikovski, M., Ji, S., McGrath, A., Custorio, M.G., Creighton, C.J., Maliakkal, P., Bogoslovskaia, E., Du, Z., Zhang, X., Lewis, M.T., Sablitzky, F., Brisken, C. & Li, Y. ID4 regulates mammary gland development by suppressing p38MAPK activity. Development 138, 5247-5256 (2011). PMID: 22069192.