The Forkhead Box Transcription Factor FOXC1 Promotes Breast Cancer Invasion by Inducing Matrix Metalloprotease 7 (MMP7) Expression

• Published in: The Journal of biological chemistry 2012-07, Vol.287 (29), p.24631-24640
• Main Authors: Sizemore, Steven T., Keri, Ruth A.
• Format: Article
• Language: English
• Subjects: Basal-like Breast Cancer; Blotting, Western; Breast Cancer; Breast Neoplasms - enzymology; Breast Neoplasms - metabolism; Cancer; Cancer Biology; Cell Line, Tumor; Cell Movement - genetics; Cell Movement - physiology; Forkhead; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; FOXC1; Gene Expression Regulation, Neoplastic - genetics; Gene Expression Regulation, Neoplastic - physiology; Gene Silencing - physiology; Humans; Invasion; Matrilysin; Matrix Metalloproteinase (MMP); Matrix Metalloproteinase 7 - genetics; Matrix Metalloproteinase 7 - metabolism; MMP7; Molecular Bases of Disease; Real-Time Polymerase Chain Reaction
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.375865

Therapeutic options for treatment of basal-like breast cancers are limited and identification of molecular targets for novel therapies to treat this aggressive cancer is urgently needed. Recently, FOXC1, a forkhead box transcription factor, was identified as a functionally important biomarker of breast cancer aggressiveness and the basal-like breast cancer subtype. However, the mechanism through which FOXC1 controls aggressiveness of basal-like breast cancer remains to be elucidated. Here, we identify matrix metalloprotease 7 (MMP7) as a key downstream effector of FOXC1-mediated invasiveness. Expression of FOXC1 and MMP7 is significantly correlated in breast cancer samples and cell lines at both the mRNA and protein levels. Transient expression of FOXC1 in nontransformed mammary epithelial cell lines resulted in significantly increased expression of MMP7 and an MMP7-dependent increase in invasiveness. In reciprocal experiments, silencing endogenous FOXC1 in basal-like breast cancer cell lines resulted in decreased expression of MMP7 without decreased expression of other matrix metalloproteinases. We also demonstrate that elevated co-expression of FOXC1 and MMP7 is an independent predictor of patient outcome in multivariate analyses of two breast cancer patient cohorts. Together, our findings identify MMP7 as a novel mechanism through which FOXC1 may regulate the basal-like breast cancer invasive phenotype and the propensity of these cancers to metastasize. Furthermore, our findings demonstrate for the first time a correlation between MMP7 expression and basal-like breast cancers, suggesting that MMP7 may be a useful therapeutic target for treatment of this disease. Background: FOXC1 is associated with breast cancer aggressiveness and the basal-like breast cancer subtype but the mechanism through which FOXC1 increases aggressiveness has not been elucidated. Results: FOXC1 induces expression of matrix metalloprotease 7 (MMP7). Conclusion: The aggressive cancer phenotype imparted by FOXC1 is due, at least in part, to expression of MMP7. Significance: MMP7 represents a putative target for the treatment of some basal-like breast cancers.