Evaluation of FOXC1 as a therapeutic target for basal-like breast cancer

Cancer Gene Ther. 2018 May;25(3-4):84-91. doi: 10.1038/s41417-018-0010-9. Epub 2018 Mar 6.

Abstract

Basal-like breast cancer (BLBC) is a malignant carcinoma with aggressive motility and rapid growth. Accounting for 15% of breast cancers, BLBC often exhibits a poor prognosis and tends to metastasize to the brain and lungs. Because most BLBC display a triple-negative phenotype (ER-, PR-, and HER2-), conventional cytotoxic chemotherapy remains the only treatment option despite poor success and high rate of relapse. The overexpression of the forkhead-box transcription factor C1 (FOXC1) was recently identified as a biomarker of BLBC. Increased expression of FOXC1 was linked to excessive mobility and growth of BLBC cell lines, suggesting FOXC1 as a therapeutic target. In this study, siRNA-mediated knockdown of FOXC1 was confirmed to decrease the proliferation rate, migration, and invasion in a model BLBC-like cell line (4T1). 4T1 and 4T1-∆FOXC1 cells lacking FOXC1 expression (generated by CRISPR/Cas9) were used to evaluate the effects of FOXC1 expression in an orthotopic murine model of BLBC. No statistically significant difference in tumor volume was observed between 4T1 and 4T1-∆FOXC1 tumors. Furthermore, tumors metastasized to the liver and lungs to a similar degree regardless of FOXC1 expression. These data suggest that, despite positive results in vitro, FOXC1 may not be a promising therapeutic target for BLBC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Female
  • Forkhead Transcription Factors* / biosynthesis
  • Forkhead Transcription Factors* / genetics
  • Gene Expression Regulation, Neoplastic*
  • Mammary Neoplasms, Animal* / genetics
  • Mammary Neoplasms, Animal* / metabolism
  • Mammary Neoplasms, Animal* / pathology
  • Mammary Neoplasms, Animal* / therapy
  • Mice
  • Neoplasm Metastasis
  • Neoplasm Proteins* / biosynthesis
  • Neoplasm Proteins* / genetics

Substances

  • Forkhead Transcription Factors
  • Foxc1 protein, mouse
  • Neoplasm Proteins