Faciogenital Dysplasia Protein Fgd1 Regulates Invadopodia Biogenesis and Extracellular Matrix Degradation and Is Up-regulated in Prostate and Breast Cancer

Abstract

Invadopodia are proteolytically active membrane protrusions that extend from the ventral surface of invasive tumoral cells grown on an extracellular matrix (ECM). The core machinery controlling invadopodia biogenesis is regulated by the Rho GTPase Cdc42. To understand the upstream events regulating invadopodia biogenesis, we investigated the role of Fgd1, a Cdc42-specific guanine nucleotide exchange factor. Loss of Fgd1 causes the rare inherited human developmental disease faciogenital dysplasia. Here, we show that Fgd1 is required for invadopodia biogenesis and ECM degradation in an invasive cell model and functions by modulation of Cdc42 activation. We also find that Fgd1 is expressed in human prostate and breast cancer as opposed to normal tissue and that expression levels matched tumor aggressiveness. Our findings suggest a central role for Fgd1 in the focal degradation of the ECM in vitro and, for the first time, show a connection between Fgd1 and cancer progression, proposing that it might function during tumorigenesis. [Cancer Res 2009;69(3):747-52]

The Aarskog-Scott Syndrome Protein Fgd1 Regulates Podosome Formation and Extracellular Matrix Remodeling in Transforming Growth Factor β-Stimulated Aortic Endothelial Cells

“…The myc-Fgd1-RKB3 fusion construct contains deletions of residues 1 to 391 and 790 at the C terminus (25,38). The GFP-Fgd1-2DBDEL fusion construct contains deletions of residues 146 to 188 and 730 at the C terminus (3,9). All Fgd1 encoding plasmids were obtained from J. L. Gorski (University of Michigan) (3).…”

A RhoG-mediated signaling pathway that modulates invadopodia dynamics in breast cancer cells

“…Invadopodia formation is controlled by the integrated activity of several GTPases, including Cdc42, RhoA, RhoC and Rac1 (Spuul et al, 2014). Cdc42 promotes invadopodia formation in almost every system tested (Ayala et al, 2009;Di Martino et al, 2014;Moreau et al, 2006Moreau et al, , 2003Nakahara et al, 2003;Tatin et al, 2006). However, generalized conclusions cannot be drawn from studies of other Rho GTPases, since their activities can both inhibit or promote invadopodia formation depending on the experimental conditions or cell type used (Spuul et al, 2014).…”

Association of FGD1 polymorphisms with early-onset breast cancer

“…For several years, FGD1 has been postulated to play a role in diseases involving protein-damaging polymorphisms, as in Aarskog-Scott syndrome, and in the somatic alterations observed in several late-stage/invasive cancer projects (8)(9)(10)12). The present study sequenced the FGD1 gene for possible somatic and germline variants that may be associated with tumor development in breast cancer patients.…”

“…A possible explanation for this difference may be that a majority (90%) of the cancer patients in this project were diagnosed with an early stage of breast cancer, with no distant tumor growth or node involvement (stage 1-2). As Fgd1 is associated with late-stage tumor development (8)(9)(10), the somatic alterations in the FGD1 gene would not have occurred until the tumor was ready to detach from the primary tumor and migrate through the tissue.…”

“…Recently, researchers have detected overexpression of the Fgd1 protein in infiltrating and poorly differentiated breast and invasive prostate tumors (8). Missense mutations in the FGD1 gene were identified in late-stage tumors of numerous types of cancer tissue, including ovarian cancer, prostate cancer, melanoma, uterine cancer, head and neck cancer (9,10).…”