BRCA1 deficiency in ovarian cancer is associated with alteration in expression of several key regulators of cell motility - A proteomics study.
Functional loss of expression of breast cancer susceptibility gene 1(BRCA1) has been implicated in genomic instability and cancer progression. There is emerging evidence that BRCA1 gene product (BRCA1) also plays a role in cancer cell migration. We performed a quantitative proteomics study of EOC patient tumor tissues and identified changes in expression of several key regulators of actin cytoskeleton/cell adhesion and cell migration (CAPN1, 14-3-3, CAPG, PFN1, SPTBN1, CFN1) associated with loss of BRCA1 function. Gene expression analyses demonstrate that several of these proteomic hits are differentially expressed between early and advanced stage EOC thus suggesting clinical relevance of these proteins to disease progression. By immunohistochemistry of ovarian tumors with BRCA1(+/+) and BRCA1(null) status, we further verified our proteomic-based finding of elevated PFN1 expression associated with BRCA1 deficiency. Finally, we established a causal link between PFN1 and BRCA1-induced changes in cell migration thus uncovering a novel mechanistic basis for BRCA1-dependent regulation of ovarian cancer cell migration. Overall, findings of this study open up multiple avenues by which BRCA1 can potentially regulate migration and metastatic phenotype of EOC cells.
a Department of Bioengineering; University of Pittsburgh ; Pittsburgh , PA , USA.
David M
DM
Gau
Jamie L
JL
Lesnock
Brian L
BL
Hood
Rohit
R
Bhargava
Mai
M
Sun
Kathleen
K
Darcy
Soumya
S
Luthra
Uma
U
Chandran
Thomas P
TP
Conrads
Robert P
RP
Edwards
Joseph L
JL
Kelley
Thomas C
TC
Krivak
Partha
P
Roy
D048948:14-3-3 Proteins / Q000378:metabolism; D008841:Actin Cytoskeleton / Q000378:metabolism; D019313:BRCA1 Protein / Q000235:genetics*; D002154:Calpain / Q000378:metabolism; D002448:Cell Adhesion; D002465:Cell Movement; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008840:Microfilament Proteins / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism*; D051304:Profilins / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000378:metabolism; D040901:Proteomics; D013049:Spectrin / Q000378:metabolism
D048948:14-3-3 Proteins; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D008840:Microfilament Proteins; D009687:Nuclear Proteins; C495738:PFN1 protein, human; D051304:Profilins; C452439:SPTBN1 protein, human; D013049:Spectrin; C066575:CAPG protein, human; D054648:Protein Phosphatase 2; D002154:Calpain; C484806:CAPN1 protein, human
BRCA1; BRCA1, Breast cancer susceptibility gene 1; BRCA2, Breast cancer susceptibility gene 2; CAPG, Macrophage capping protein; CAPN1, Calpain-1; CFN1, Cofilin-1; EOC, Epithelial Ovarian Cancer; ERM, Ezrin-Radixin-Moesin; FFPE, Formalin-fixed paraffin-embedded; HYOU1, Hypoxia upregulated protein 1; ID1, Inhibitor of differentiation-1; IHC, Immunohistochemistry; LC MS-MS, Liquid chromatography tandem mass spectrometry; Luc, luciferase; PFN1, Profilin-1; PP2A, Protein phosphatase 2A; SPTBN1, Non-erythrocytic spectrin β Chain-1; WT, Wild-type; cell Motility; ovarian cancer; profilin-1