The long term goal of the proposed studies is to understand the signal transduction mechanisms in cancer development and progression. The previous funding period focused on the role of focal adhesion kinase (FAK) and several other proteins in the regulation of cell migration and breast cancer development and metastasis. We have illustrated the mechanisms by which FAK-mediated Src phosphorylation of endophilin A2 inhibits endocytosis of MT1-MMP to stimulate cancer cell invasion. Using a conditional KO approach, we showed that mammary epithelial-specific deletion of FAK leads to severe lobulo-alveolar hypoplasia and secretory immaturity of the murine mammary gland. Furthermore, we demonstrated that inactivation of FAK in mammary epithelial cells suppresses mammary tumorigenesis and progression by affecting mammary cancer stem/progenitor cells using the well-characterized MMTV-PyMT mouse model of human breast cancer. We also created the defined fibronectin gradients using microfluidics approaches and analyzed the role of FAK and a number of other signaling molecules in the regulation of directional cell migration. Additional studies identified a novel interaction between N-WASP and hnRNPK and showed that hnRNPK may function as a negative regulator of N-WASP to inhibit filopodia formation and cell spreading. This grant also supported our work on the role of nuclear localized actin regulatory proteins N-WASP and Arp2/3 complex in the regulation of RNA polymerase II- dependent transcription. In preliminary studies, we made the unexpected finding that inactivation of FIP200, a putative breast tumor suppressor based on initial studies in cancer cell lines, inhibits (rather than promotes) mammary tumorigenesis and progression in the MMTV-PyMT mouse model of breast cancer in vivo. We further showed that both intrinsic proliferative defects of FIP200-null mammary tumor cells as well as increased infiltration of immune cells in the tumor microenvironment may contribute to the suppression of mammary tumorigenesis and progression in MMTV- PyMT mice with conditional KO of FIP200. Based on these preliminary studies, we propose to determine the mechanisms by which FIP200 and its associated signaling pathways regulate breast cancer development and progression using a combination of molecular, cellular, immunological and mouse genetic approaches. We will 1). analyze molecular mechanisms of FIP200 regulation of mammary tumor cell proliferation using primary culture of isolated tumor cells, 2). examine the role and mechanisms of elevated immune cell infiltration in the suppression of mammary tumor development upon FIP200 ablation, and 3). investigate the potential role of FIP200 in mammary tumor maintenance.

Public Health Relevance

Breast cancer is the most common malignancy among US women and a major health threat due to its high incidents and death rate. Analysis of molecular and cellular mechanisms by which key signaling molecules and their associated pathways and cellular processes regulate breast cancer development and progression using mouse models in vivo will significantly advance our understanding of the basic mechanisms of breast cancer that may contribute to novel therapies for the devastating disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA150926-22
Application #
8593277
Study Section
Intercellular Interactions (ICI)
Program Officer
Mohla, Suresh
Project Start
1992-08-01
Project End
2014-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
22
Fiscal Year
2014
Total Cost
$254,311
Indirect Cost
$86,150
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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 Tgfβ/Smad Signaling. Cancer Res 76:3397-410
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
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 28:758-72
Wen, Jian; Yeo, Syn; Wang, Chenran et al. (2015) Autophagy inhibition re-sensitizes pulse stimulation-selected paclitaxel-resistant triple negative breast cancer cells to chemotherapy-induced apoptosis. Breast Cancer Res Treat 149:619-29
Wei, Huijun; Wang, Chenran; Croce, Carlo M et al. (2014) p62/SQSTM1 synergizes with autophagy for tumor growth in vivo. Genes Dev 28:1204-16
Chen, Yongqiang; Wei, Huijun; Liu, Fei et al. (2014) Hyperactivation of mammalian target of rapamycin complex 1 (mTORC1) promotes breast cancer progression through enhancing glucose starvation-induced autophagy and Akt signaling. J Biol Chem 289:1164-73
Fan, Huaping; Zhao, Xiaofeng; Sun, Shaogang et al. (2013) Function of focal adhesion kinase scaffolding to mediate endophilin A2 phosphorylation promotes epithelial-mesenchymal transition and mammary cancer stem cell activities in vivo. J Biol Chem 288:3322-33
Chen, Song; Guan, Jun-Lin (2013) Tumor-promoting and -suppressive roles of autophagy in the same mouse model of BrafV600E-driven lung cancer. Cancer Discov 3:1225-7
Liu, Fei; Fang, Fang; Yuan, Hebao et al. (2013) Suppression of autophagy by FIP200 deletion leads to osteopenia in mice through the inhibition of osteoblast terminal differentiation. J Bone Miner Res 28:2414-30
Luo, Ming; Zhao, Xiaofeng; Chen, Song et al. (2013) Distinct FAK activities determine progenitor and mammary stem cell characteristics. Cancer Res 73:5591-602

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