Breast cancer exhibits enormous cellular, genomic and biological complexity wherein multiple gene aberrations act to drive tumorigenesis and cancer progression. The long term goal of the proposed studies is to understand the cellular and molecular mechanisms in the regulation of breast cancer development and metastasis. Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that plays a major role in mediating signal transduction by integrins as well as growth factor receptors in the regulation of cell adhesion, migration, survival, proliferation and differentiation in a variety of cells. FAK has been implicated in human breast cancer as well as other malignancies. However, the cellular and molecular mechanisms by which FAK promotes mammary tumorigenesis in vivo are still not well understood. We showed recently that conditional knockout of FAK in the mammary epithelium suppressed mammary tumorigenesis and progression by affecting MaCSCs in a well characterized breast cancer mouse model. To investigate the unique role of FAK as both a tyrosine kinase and a scaffold in intracellular signaling in breast cancer, we have recently created two novel FAK knock-in mutant mice with the kinase-defective allele (FAK +/KD mice) or the P878/881A mutation allele (FAK +/PA mice) to disrupt its signaling through tyrosine kinase activity or specific scaffolding function for endophilin A2 phosphorylation by Src and regulation of MT1-MMP, respectively. Preliminary analyses of the PA mutant knockin mice using the MMTV-PyMT model (PA/PA-MT mice) revealed that FAK mediated endophilin A2 phosphorylation by Src plays an important role in mammary tumor growth and metastasis by promoting epithelial to mesenchymal transition (EMT) of mammary tumor cells, and by maintaining the content and tumorigenicity of MaCSCs. In addition, we identified a function of FAK in the maintenance of normal MaSCs and found that kinase-independent functions of FAK were able to promote self-renewal of MaSCs. Lastly, we also obtained preliminary results suggesting an important role of FAK in regulation of human MaCSCs, which is consistent with our more extensive findings in mouse models. Based on these preliminary and previous studies, we propose to 1). determine the mechanism of FAK scaffold function in mammary tumor growth and metastasis through regulation of EMT and MaCSCs, 2). examine the role of FAK kinase activity and dissect the downstream kinase-dependent and -independent signaling pathways in breast cancer development and progression, and 3). explore the strategies of targeting FAK scaffold and kinase functions in MaCSCs for breast cancer therapy. Together, these studies will provide significant insights into the molecular and cellular mechanisms of breast cancer that may contribute to novel therapies for this devastating disease.

Public Health Relevance

Breast cancer is the most common malignancy among US women and a major health threat due to its high incidence and mortality from the disease. The characterization of key signaling proteins and pathways that regulate mammary tumorigenesis and progression will significantly advance our understanding of the molecular and cellular mechanisms of breast cancer that may contribute to novel and targeted therapies to eradicate breast cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Woodhouse, Elizabeth
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
Zip Code
Huang, Huilin; Weng, Hengyou; Sun, Wenju et al. (2018) Recognition of RNA N6-methyladenosine by IGF2BP proteins enhances mRNA stability and translation. Nat Cell Biol 20:285-295
Yeo, Syn Kok; Guan, Jun-Lin (2017) Breast Cancer: Multiple Subtypes within a Tumor? Trends Cancer 3:753-760
He, Yun; Sun, Xiumei; Wang, Li et al. (2017) Male germline recombination of a conditional allele by the widely used Dermo1-cre (Twist2-cre) transgene. Genesis 55:
Wang, Chenran; Yeo, Syn; Haas, Michael A et al. (2017) Autophagy gene FIP200 in neural progenitors non-cell autonomously controls differentiation by regulating microglia. J Cell Biol 216:2581-2596
Sun, Chunhui; Yuan, Hebao; Wang, Li et al. (2016) FAK Promotes Osteoblast Progenitor Cell Proliferation and Differentiation by Enhancing Wnt Signaling. J Bone Miner Res 31:2227-2238
Chen, Song; Wang, Chenran; Yeo, Syn et al. (2016) Distinct roles of autophagy-dependent and -independent functions of FIP200 revealed by generation and analysis of a mutant knock-in mouse model. Genes Dev 30:856-69
Wang, Chenran; Chen, Song; Yeo, Syn et al. (2016) Elevated p62/SQSTM1 determines the fate of autophagy-deficient neural stem cells by increasing superoxide. J Cell Biol 212:545-60
Yeo, Syn Kok; Wen, Jian; Chen, Song et al. (2016) Autophagy Differentially Regulates Distinct Breast Cancer Stem-like Cells in Murine Models via EGFR/Stat3 and Tgf?/Smad Signaling. Cancer Res 76:3397-410
Sun, Shaogang; Chen, Song; Liu, Fei et al. (2015) Constitutive Activation of mTORC1 in Endothelial Cells Leads to the Development and Progression of Lymphangiosarcoma through VEGF Autocrine Signaling. Cancer Cell 28:758-772
Wei, Huijun; Guan, Jun-Lin (2015) Blocking tumor growth by targeting autophagy and SQSTM1 in vivo. Autophagy 11:854-5

Showing the most recent 10 out of 17 publications