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Barrios J, Wieder R. Dual FGF-2 and intergrin alpha5beta1 signaling mediate GRAF-induced RhoA inactivation in a model of breast cancer dormancy. Cancer Microenviron. 2009;2(1):33-47doi: 10.1007/s12307-009-0019-6.
Barrios, J., & Wieder, R. (2009). Dual FGF-2 and intergrin alpha5beta1 signaling mediate GRAF-induced RhoA inactivation in a model of breast cancer dormancy. Cancer microenvironment : official journal of the International Cancer Microenvironment Society, 2(1), 33-47. https://doi.org/10.1007/s12307-009-0019-6
Barrios, Judith, and Wieder, Robert. "Dual FGF-2 and intergrin alpha5beta1 signaling mediate GRAF-induced RhoA inactivation in a model of breast cancer dormancy." Cancer microenvironment : official journal of the International Cancer Microenvironment Society vol. 2,1 (2009): 33-47. doi: https://doi.org/10.1007/s12307-009-0019-6
Barrios J, Wieder R. Dual FGF-2 and intergrin alpha5beta1 signaling mediate GRAF-induced RhoA inactivation in a model of breast cancer dormancy. Cancer Microenviron. 2009 Dec;2(1):33-47. doi: 10.1007/s12307-009-0019-6. Epub 2009 Mar 18. PMID: 19308677; PMCID: PMC2787927.
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Cancer Microenviron. 2009 Dec;2(1):33-47. doi: 10.1007/s12307-009-0019-6. Epub 2009 Mar 18.

Dual FGF-2 and intergrin alpha5beta1 signaling mediate GRAF-induced RhoA inactivation in a model of breast cancer dormancy.

Cancer microenvironment : official journal of the International Cancer Microenvironment Society

Judith Barrios, Robert Wieder

Affiliations

  1. Department of Medicine, UMDNJ-New Jersey Medical School-University Hospital Cancer Center, CCH1216, Newark, NJ 07103, USA.

PMID: 19308677 PMCID: PMC2787927 DOI: 10.1007/s12307-009-0019-6

Abstract

Interactions with the bone marrow stroma regulate dormancy and survival of breast cancer micrometastases. In an in vitro model of dormancy in the bone marrow, we previously demonstrated that estrogen-dependent breast cancer cells are partially re-differentiated by FGF-2, re-express integrin alpha5beta1 lost with malignant transformation and acquire an activated PI3K/Akt pathway. Ligation of integrin alpha5beta1 by fibronectin and activation of the PI3K pathway both contribute to survival of these dormant cells. Here, we investigated mechanisms responsible for the dormant phenotype. Experiments demonstrate that integrin alpha5beta1 controls de novo cytoskeletal rearrangements, cell spreading, focal adhesion kinase rearrangement to the cell perimeter and recruitment of a RhoA GAP known as GRAF. This results in the inactivation of RhoA, an effect which is necessary for the stabilization of cortical actin. Experiments also demonstrate that activation of the PI3K pathway by FGF-2 is independent of integrin alpha5beta1 and is also required for cortical actin reorganization, GRAF membrane relocalization and RhoA inactivation. These data suggest that GRAF-mediated RhoA inactivation and consequent phenotypic changes of dormancy depend on dual signaling by FGF-2-initiated PI3K activation and through ligation of integrin alpha5beta1 by fibronectin.

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