Yi Li, Ph.D.
Department of Molecular and Cellular Biology
Lester and Sue Smith Breast Center
- B.S. Department of Animal Science and Veterinary Medicine, Jiangsu Agricultural College, China
- M.S. Department of Animal Science and Veterinary Medicine, Jiangsu Agricultural College, China
- Ph.D. Department of Microbiology, Michigan State University
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.
- Du Z, Podsypanina K, Huang S, McGrath A, Toneff MJ, Bogoslovskaia E, Zhang X, Moraes RC, Fluck M, Allred DC, Lewis MT, Varmus HE, Li Y. (2006). Rapid induction of mammary tumorigenesis by somatic introduction of an oncogene into individual mammary epithelial cells in vivo. PNAS. 103: 17396-17401.
- Lindvall C, Evans NC, Zylstra CR, Li Y, Alexander CM, Williams BO. (2006). The WNT signaling receptor, LRP5, is required for mammary ductal stem cell activity and WNT1-induced tumorigenesis. JBC. 281(46):35081-7.
- Huang S, Li Y, Chen Y, Podsypanina K, Chamorro M, Olshen AB, Desai KV, Tann A, Petersen D, Green JE, Varmus HE. (2005). Changes in gene expression during the development of mammary tumors in MMTV-Wnt-1 transgenic mice. Genome Biology. 6:R84.
- Zhang X, Podsypanina K, Huang S, Mohsin SK, Chamness GC, Hatsell S, Cowin P, Schiff R, and Li Y. (2005). Estrogen receptor positivity in mammary tumors of Wnt-1 transgenic mice is influenced by collaborating oncogenic mutations. Oncogene 24: 4220-4231.
- Hu X, Pandolfi PP, Li Y, Koutcher JA, Rosenblum, M, Holland EC. (2005). mTOR promotes survival and astrocytic characteristics induced by Pten/AKT signaling in glioblastoma. Neoplasia, 7: 356-68.
- Podsypanina K, Li Y and Varmus HE (2004). Evolution of somatic mutations in mammary tumors in transgenic mice is influenced by the inherited genotype. BMC Medicine, 2:24.
- Sodhi A, Montaner S, Patel V, Gomez-Roman JJ, Li Y, Sausville EA, Sawai ET, Gutkind JS. (2004) Akt Plays a Central Role in vGPCR-Induced Sarcomagenesis: A Novel Therapeutic Target for Kaposi's Sarcoma. PNAS, 101: 4821-4826.
- Li Y Welm B, Podsypanina K, Huang S, Chamorro M, Zhang X, Rowlands R, Egeblad M, Cowin P, Werb Z, Tan LK, Rosen JM and Varmus HE. (2003) Evidence that transgenes encoding components of the Wnt signaling pathway preferentially induce mouse mammary cancers from early cells in mammary development. PNAS. 100: 15853-15858.
- Montaner S, Sodhi A, Molinolo A, Bugge TH, Sawai ET, He Y, Li Y, Ray PE and JS Gutkind. (2003) Endothelial infection with KSHV genes in vivo reveals that vGPCR initiates Kaposi's sarcomagenesis and can promote the tumorigenic potential of viral latent genes. Cancer Cell. 3:23-36.
- Orsulic S, Li Y, Soslow RA, Vitale-Cross LA, Gutkind JS and Varmus HE. (2002) Induction of ovarian cancer by defined multiple genetic changes in a mouse model system. Cancer Cell, 1: 53-62.