The majority of breast cancer deaths are directly due to tumor dissemination through invasion and metastasis. Cell motility is a fundamental and indispensable aspect of both tumor cell invasion and metastasis. As such, cell motility is an excellent target for therapeutic intervention with the potential to decrease breast cancer patient morbidity and mortality. To better understand motility, we studyintegrins, which are receptors for the extracellular matrix that transduce signals that are critical for cell motility. Recently, integrins have been shown to regulate Protein Kinase A (PKA). Importantly, this regulation of PKA is critical for cell motility due to the involvement of PKA in the control of Rac and Rho GTPases. However, the mechanisms governing integrin regulation of PKA and how PKA regulates Rac and Rho are unclear. The long-term goal of this project is to understand how integrins and their control of PKA activity promote carcinoma cell invasion so that PKA activity may be properly targeted for therapeutic intervention. The objective of this proposal is to understand how pi integrin regulation of PKA activitycontrols Rac and Rho small GTPases in the chemotactic migration of carcinoma cells.
Our first aim i s to determine how pi integrins regulate PKA. Our next two aims are designed to elucidate the mechanisms by whichPKA activity regulates the activities of RhoA and Racl. In our fourth aim, we will identify which PKA subunits are associated with breast cancer cell motility and dissemination using surgical samples, in vitro motility and invasion assays and animal models. With the results from this proposal, we expect to delineate the signaling molecules upstream and downstream of PKA that are required for cell migration so that we can intelligently target PKA for therapeutic intervention of late stage cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA109136-03
Application #
7336346
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Woodhouse, Elizabeth
Project Start
2006-03-09
Project End
2010-12-31
Budget Start
2008-01-01
Budget End
2008-12-31
Support Year
3
Fiscal Year
2008
Total Cost
$260,253
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Surgery
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Xiong, Gaofeng; Stewart, Rachel L; Chen, Jie et al. (2018) Collagen prolyl 4-hydroxylase 1 is essential for HIF-1? stabilization and TNBC chemoresistance. Nat Commun 9:4456
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Yin, Yuanqin; Deng, Xinyu; Liu, Zeyi et al. (2014) CD151 represses mammary gland development by maintaining the niches of progenitor cells. Cell Cycle 13:2707-22
Harrison, Susan M W; Knifley, Teresa; Chen, Min et al. (2013) LPA, HGF, and EGF utilize distinct combinations of signaling pathways to promote migration and invasion of MDA-MB-231 breast carcinoma cells. BMC Cancer 13:501
Chen, M; Bresnick, A R; O'Connor, K L (2013) Coupling S100A4 to Rhotekin alters Rho signaling output in breast cancer cells. Oncogene 32:3754-64

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