The objective of this application is to define the mechanisms by which the NFAT transcription factor promotes breast cancer cell invasive migration. Specifically, we will focus on the signaling pathways stimulated by genes induced by NFAT and which promote invasive migration. Studies in the previous funding period showed that NFAT is a critical transcription factor in cancer cells as it promotes both the motility and invasion of carcinoma cells. We showed that the ?6?4 integrin is one important upstream regulatory mechanism leading to NFAT activation, and also published the role of Akt/PKB and GSK-3 in NFAT regulation. Little is known, however, concerning the array of genes induced by NFAT, and how in turn these genes control invasive migration. Recent published and preliminary studies have provided evidence that COX-2 (cyclooxygenase-2) is an NFAT-induced gene which promotes carcinoma invasion. We have further identified two families of cell surface receptors, chemokine receptors and glypicans (heparan sulfate proteoglycans) which are induced by NFAT, and studies show that they promote invasive migration. We propose the hypothesis that NFAT promotes invasive migration by inducing paracrine and autocrine signaling pathways whereby both chemokine ligands, chemokine receptors and glypicans are critical modulators of this phenotype. There is near complete paucity of knowledge concerning the nature of genes induced by NFAT in cancer, and our studies take a discovery-based approach to identify, characterize and investigate in detail the molecular mechanisms by which transcriptional responses induced by NFAT modulate cancer cell signaling. Our overall hypothesis will be tested in 2 specific Aims.:- In AIM 1 we will test the contribution chemokine receptors and chemokines induced by NFAT in breast cancer cells. We will determine the contribution of chemokine receptors including CXCR-2, CCR-2, XCR-1 and CXCR4 and their ligands in NFAT-mediated invasion, and the role of paracrine and autocrine signaling.
In AIM 2, we will determine the mechanism by which NFAT induces glypican-6 (GPC6) expression. We will determine how NFAT and GPC6 promote invasive migration in vitro and in vivo, and investigate the mechanisms by which GPC6 collaborates with Wnt signaling. The results of these studies will provide important new insights into the mechanisms by which NFAT modulates cancer cell invasive migration through induction of critical target genes. We anticipate that continuation of our NFAT studies will provide important new information in the field because they will highlight new mechanisms of modulation of cancer progression. There is also the potential that the outcome of our studies will provide for the future development of therapeutic interventions for tumor progression.

Public Health Relevance

NFAT is a cellular protein which plays a key role in mediating the motility of cancer cells leading to metastasis to distant organs. Relatively little information is known regarding the mechanisms by which NFAT regulated the ability of breast cancer cells to migrate and become invasive, two features which are critical for the metastasis of breast tumors in humans. The overall goal of the application is to dissect the functions of NFAT in modulating breast cancer progression, leading to metastasis, which is a major impediment in the effective treatment of cancer in the present day. It is expected that a greater understanding of breast cancer cell invasion can contribute to the design of more effective anti-cancer drugs.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA096710-09
Application #
8235972
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Snyderwine, Elizabeth G
Project Start
2002-07-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
9
Fiscal Year
2012
Total Cost
$295,224
Indirect Cost
$121,563
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Yiu, Gary K; Kaunisto, Aura; Chin, Y Rebecca et al. (2011) NFAT promotes carcinoma invasive migration through glypican-6. Biochem J 440:157-66
Fry, Jessica L; Toker, Alex (2010) Secreted and membrane-bound isoforms of protease ADAM9 have opposing effects on breast cancer cell migration. Cancer Res 70:8187-98
Mancini, Maria; Toker, Alex (2009) NFAT proteins: emerging roles in cancer progression. Nat Rev Cancer 9:810-20
Yoeli-Lerner, Merav; Chin, Y Rebecca; Hansen, Christopher K et al. (2009) Akt/protein kinase b and glycogen synthase kinase-3beta signaling pathway regulates cell migration through the NFAT1 transcription factor. Mol Cancer Res 7:425-32
Yiu, Gary K; Toker, Alex (2006) NFAT induces breast cancer cell invasion by promoting the induction of cyclooxygenase-2. J Biol Chem 281:12210-7
Mazzocca, Antonio; Coppari, Roberto; De Franco, Raffaella et al. (2005) A secreted form of ADAM9 promotes carcinoma invasion through tumor-stromal interactions. Cancer Res 65:4728-38