FOXC1 Is a Potential Prognostic Biomarker with Functional Significance in Basal-like Breast Cancer

Department of Surgical Oncology, John Wayne Cancer Institute, Santa Monica, California 90404, USA.
Cancer Research (Impact Factor: 9.28). 05/2010; 70(10):3870-6. DOI: 10.1158/0008-5472.CAN-09-4120
Source: PubMed

ABSTRACT Gene expression signatures for a basal-like breast cancer (BLBC) subtype have been associated with poor clinical outcomes, but a molecular basis for this disease remains unclear. Here, we report overexpression of the transcription factor FOXC1 as a consistent feature of BLBC compared with other molecular subtypes of breast cancer. Elevated FOXC1 expression predicted poor overall survival in BLBC (P = 0.0001), independently of other clinicopathologic prognostic factors including lymph node status, along with a higher incidence of brain metastasis (P = 0.02) and a shorter brain metastasis-free survival in lymph node-negative patients (P < 0.0001). Ectopic overexpression of FOXC1 in breast cancer cells increased cell proliferation, migration, and invasion, whereas shRNA-mediated FOXC1 knockdown yielded opposite effects. Our findings identify FOXC1 as a theranostic biomarker that is specific for BLBC, offering not only a potential prognostic candidate but also a potential molecular therapeutic target in this breast cancer subtype.

Download full-text


Available from: Ying Qu, Mar 02, 2014
1 Follower
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In this study we describe a novel interaction between the breast/ovarian tumor suppressor gene BRCA1 and the transcription factor GATA3, an interaction, which is important for normal breast differentiation. We show that the BRCA1-GATA3 interaction is important for the repression of genes associated with triple-negative and basal-like breast cancer (BLBCs) including FOXC1, and that GATA3 interacts with a C-terminal region of BRCA1. We demonstrate that FOXC1 is an essential survival factor maintaining the proliferation of BLBCs cell lines. We define the mechanistic basis of this corepression and identify the GATA3-binding site within the FOXC1 distal promoter region. We show that BRCA1 and GATA3 interact on the FOXC1 promoter and that BRCA1 requires GATA3 for recruitment to this region. This interaction requires fully functional BRCA1 as a mutant BRCA1 protein is unable to localize to the FOXC1 promoter or repress FOXC1 expression. We demonstrate that this BRCA1-GATA3 repression complex is not a FOXC1-specific phenomenon as a number of other genes associated with BLBCs such as FOXC2, CXCL1 and p-cadherin were also repressed in a similar manner. Finally, we demonstrate the importance of our findings by showing that loss of GATA3 expression or aberrant FOXC1 expression contributes to the drug resistance and epithelial-to-mesenchymal transition-like phenotypes associated with aggressive BLBCs.
    Oncogene 11/2011; 31(32):3667-78. DOI:10.1038/onc.2011.531 · 8.56 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease with a high proliferation rate. However, the molecular and genetic features that drive the aggressive clinical behavior of DLBCL are not fully defined. Here, we have demonstrated that activated Jun signaling is a frequent event in DLBCL that promotes dissemination of malignant cells. Down-regulation of Jun dramatically reduces lymphoma cell adhesion to extracellular matrix proteins, subcutaneous tumor size in nude mice, and invasive behavior, including bone marrow infiltration and interaction with bone marrow stromal cells. Furthermore, using a combination of RNA interference and gene expression profiling, we identified Jun target genes that are associated with disseminated lymphoma. Among them, ITGAV, FoxC1 and CX3CR1 are significantly enriched in patients with two or more extranodal sites. Our results point to activated Jun signaling as a major driver of the aggressive phenotype of DLBCL. Copyright © 2014 American Society of Hematology.
    Blood 12/2014; 125(6). DOI:10.1182/blood-2014-04-568188 · 9.78 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: BRAF mutations are frequent in cutaneous melanomas and BRAF inhibitors(BRAFi) have shown remarkable clinical efficacy in BRAF mutant melanoma patients. However, acquired drug resistance can occur rapidly and tumor(s) often progress thereafter. Various mechanisms of BRAFi resistance have recently been described; however, the mechanism of resistance remains controversial. In this study we developed BRAFi resistant melanoma cell lines and found that metastasis related EMT properties of BRAFi resistant cells were enhanced significantly. Upregulation of EGFR was observed in BRAFi resistant cell lines and patient tumors due to demethylation of EGFR regulatory DNA elements. EGFR induced PI3K/AKT pathway activation in BRAFi resistant cells through epigenetic regulation. Treatment of EGFR inhibitor was effective in BRAFi resistant melanoma cell lines. The study demonstrates that EGFR epigenetic activation has important implications in BRAFi resistance in melanoma.Journal of Investigative Dermatology accepted article preview online, 22 September 2014. doi:10.1038/jid.2014.418.
    Journal of Investigative Dermatology 09/2014; DOI:10.1038/jid.2014.418 · 6.37 Impact Factor