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 #
7R01CA109136-05
Application #
8005849
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Woodhouse, Elizabeth
Project Start
2006-03-09
Project End
2012-03-31
Budget Start
2010-02-23
Budget End
2012-03-31
Support Year
5
Fiscal Year
2010
Total Cost
$268,826
Indirect Cost
Name
University of Kentucky
Department
Biochemistry
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
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
Stewart, Rachel L; Carpenter, Brittany L; West, Dava S et al. (2016) S100A4 drives non-small cell lung cancer invasion, associates with poor prognosis, and is effectively targeted by the FDA-approved anti-helminthic agent niclosamide. Oncotarget 7:34630-42
Stewart, Rachel L; West, Dava; Wang, Chi et al. (2016) Elevated integrin ?6?4 expression is associated with venous invasion and decreased overall survival in non-small cell lung cancer. Hum Pathol 54:174-83
Carpenter, Brittany L; Chen, Min; Knifley, Teresa et al. (2015) Integrin ?6?4 Promotes Autocrine Epidermal Growth Factor Receptor (EGFR) Signaling to Stimulate Migration and Invasion toward Hepatocyte Growth Factor (HGF). J Biol Chem 290:27228-38
Stewart, Rachel L; O'Connor, Kathleen L (2015) Clinical significance of the integrin ?6?4 in human malignancies. Lab Invest 95:976-86
Chen, Min; Knifley, Teresa; Subramanian, Thangaiah et al. (2014) Use of synthetic isoprenoids to target protein prenylation and Rho GTPases in breast cancer invasion. PLoS One 9:e89892
Zaytseva, Yekaterina Y; Elliott, Victoria A; Rychahou, Piotr et al. (2014) Cancer cell-associated fatty acid synthase activates endothelial cells and promotes angiogenesis in colorectal cancer. Carcinogenesis 35:1341-51
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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