The SLUG zinc-finger protein represses E-cadherin in breast cancer.
Loss of expression of the E-cadherin cell-cell adhesion molecule is important in carcinoma development and progression. Because previous data suggest that loss of E-cadherin expression in breast carcinoma may result from a dominant transcriptional repression pathway acting on the E-cadherin proximal promoter, we pursued studies of cis sequences and transcription factors regulating E-cadherin expression in breast cancer cells. E-box elements in the E-cadherin promoter were found to play a critical negative regulatory role in E-cadherin gene transcription in breast cancer cell lines lacking E-cadherin transcription. The E-box elements had a minimal role in E-cadherin transcription in breast cancer cell lines expressing E-cadherin. Two zinc-finger transcription factors known to bind E-box elements, SLUG and SNAIL, repressed E-cadherin-driven reporter gene constructs containing wild-type promoter sequences but not those with mutations in the E-box elements. Additionally, both SLUG and SNAIL repressed endogenous E-cadherin expression. These findings suggest SLUG and SNAIL are potential repressors of E-cadherin transcription in carcinomas lacking E-cadherin expression. Analysis of the expression patterns of SLUG, SNAIL, and E-cadherin in breast cancer cell lines demonstrated that expression of SLUG was strongly correlated with loss of E-cadherin transcripts. Taken together, the data indicate the E-box elements in the proximal E-cadherin promoter are critical in transcriptional repression of the E-cadherin gene, and SLUG is a likely in vivo repressor of E-cadherin in breast cancer.
Hajra
Karen M
KM
Program in Cellular and Molecular Biology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Chen
David Y-S
DY
Fearon
Eric R
ER
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D015820:Cadherins / Q000096:biosynthesis* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D024721:E-Box Elements / Q000235:genetics; D006801:Humans; D011401:Promoter Regions, Genetic / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology; D014407:Tumor Cells, Cultured; D016335:Zinc Fingers
D015820:Cadherins; D004268:DNA-Binding Proteins; D012097:Repressor Proteins; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors