Homeoprotein Six2 promotes breast cancer metastasis via transcriptional and epigenetic control of E-cadherin expression

Chu An Wang, David Drasin, Catherine Pham, Paul Jedlicka, Vadym Zaberezhnyy, Michelle Guney, Howard Li, Raphael Nemenoff, James C. Costello, Aik-Choon Tan, Heide L. Ford

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Misexpression of developmental transcription factors occurs often in human cancers, where embryonic programs may be reinstated in a context that promotes or sustains malignant development. In this study, we report the involvement of the kidney development transcription factor Six2 in the metastatic progression of human breast cancer. We found that Six2 promoted breast cancer metastasis by a novel mechanism involving both transcriptional and epigenetic regulation of E-cadherin. Downregulation of E-cadherin by Six2 was necessary for its ability to increase soft agar growth and in vivo metastasis in an immunocompetent mouse model of breast cancer. Mechanistic investigations showed that Six2 represses E-cadherin expression by upregulating Zeb2, in part, through a microRNA-mediated mechanism and by stimulating promoter methylation of the E-cadherin gene (Cdh1). Clinically, SIX2 expression correlated inversely with CDH1 expression in human breast cancer specimens, corroborating the disease relevance of their interaction. Our findings establish Six2 as a regulator of metastasis in human breast cancers and demonstrate an epigenetic function for SIX family transcription factors in metastatic progression through the regulation of E-cadherin.

Original languageEnglish
Pages (from-to)7357-7370
Number of pages14
JournalCancer Research
Volume74
Issue number24
DOIs
Publication statusPublished - 2014 Dec 15
Externally publishedYes

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Homeodomain Proteins
Cadherins
Epigenomics
Breast Neoplasms
Neoplasm Metastasis
Transcription Factors
MicroRNAs
Methylation
Agar
Down-Regulation
Kidney
Growth
Genes
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Wang, C. A., Drasin, D., Pham, C., Jedlicka, P., Zaberezhnyy, V., Guney, M., ... Ford, H. L. (2014). Homeoprotein Six2 promotes breast cancer metastasis via transcriptional and epigenetic control of E-cadherin expression. Cancer Research, 74(24), 7357-7370. https://doi.org/10.1158/0008-5472.CAN-14-0666

Homeoprotein Six2 promotes breast cancer metastasis via transcriptional and epigenetic control of E-cadherin expression. / Wang, Chu An; Drasin, David; Pham, Catherine; Jedlicka, Paul; Zaberezhnyy, Vadym; Guney, Michelle; Li, Howard; Nemenoff, Raphael; Costello, James C.; Tan, Aik-Choon; Ford, Heide L.

In: Cancer Research, Vol. 74, No. 24, 15.12.2014, p. 7357-7370.

Research output: Contribution to journalArticle

Wang, CA, Drasin, D, Pham, C, Jedlicka, P, Zaberezhnyy, V, Guney, M, Li, H, Nemenoff, R, Costello, JC, Tan, A-C & Ford, HL 2014, 'Homeoprotein Six2 promotes breast cancer metastasis via transcriptional and epigenetic control of E-cadherin expression', Cancer Research, vol. 74, no. 24, pp. 7357-7370. https://doi.org/10.1158/0008-5472.CAN-14-0666
Wang, Chu An ; Drasin, David ; Pham, Catherine ; Jedlicka, Paul ; Zaberezhnyy, Vadym ; Guney, Michelle ; Li, Howard ; Nemenoff, Raphael ; Costello, James C. ; Tan, Aik-Choon ; Ford, Heide L. / Homeoprotein Six2 promotes breast cancer metastasis via transcriptional and epigenetic control of E-cadherin expression. In: Cancer Research. 2014 ; Vol. 74, No. 24. pp. 7357-7370.
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