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Extinction of E-cadherin expression in breast cancer via a dominant repression pathway acting on proximal promoter
1Program in Cellular and Molecular Biology, University of Michigan Medical School, Ann Arbor, Michigan, MI 48109 USA.
Abstract:
Inactivation of the E-cadherin cell adhesion molecule is believed critical in the development and behavior of many epithelial cancers, though mutations in the E-cadherin gene account for inactivation in only a fraction of cases. In many breast cancer lines, E-cadherin transcription is extinguished, but the role and significance of alterations in trans-acting transcription factors, promoter hypermethylation, and chromatin changes remain unresolved. To gain further insights into mechanisms underlying E-cadherin inactivation in breast cancer, we analysed somatic cell hybrids resulting from pairwise fusions between breast cancer lines with intact E-cadherin transcription (E-cad+) and lines lacking E-cadherin transcription (E-cad-). All hybrid lines failed to express E-cadherin transcripts and protein, despite the fact that E-cadherin alleles from E-cad+ lines were present in the hybrids. Elements in the proximal 108 bp of the E-cadherin promoter, when present in reporter gene constructs, were sufficient to direct strong transcription in E-cad+ breast lines, but displayed weak activity in E-cad- parental lines and hybrids. E-cadherin expression could not be restored in E-cad- lines or hybrids by treatment with a DNA demethylating agent and/or a histone deacetylase inhibitor. Our findings suggest loss of E-cadherin expression in some breast cancers may be due to dominant repression of the trans-acting pathways that regulate E-cadherin transcription.
Insights
Loss of E-cadherin expression in breast cancer is common, but gene mutations are rare. This study reveals dominant repression of transcription factors, not genetic or epigenetic changes, likely causes E-cadherin inactivation in some cancers.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Adhesion
Background:
- E-cadherin inactivation is critical in epithelial cancers, but gene mutations explain only a fraction of cases.
- Mechanisms like altered transcription factors, hypermethylation, and chromatin changes are implicated but unresolved in breast cancer.
- E-cadherin (epithelial cadherin) is a key cell adhesion molecule.
Purpose of the Study:
- Investigate mechanisms of E-cadherin inactivation in breast cancer.
- Identify factors contributing to extinguished E-cadherin transcription in breast cancer lines.
- Clarify the role of trans-acting factors, promoter methylation, and chromatin modifications.
Main Methods:
- Analysis of somatic cell hybrids from fusions between E-cadherin-expressing (E-cad+) and non-expressing (E-cad-) breast cancer lines.
- Reporter gene assays using the proximal 108 bp of the E-cadherin promoter.
- Treatment of cell lines with DNA demethylating agents and histone deacetylase inhibitors.
Main Results:
- All hybrid lines, regardless of parental E-cadherin status, failed to express E-cadherin transcripts and protein.
- The proximal E-cadherin promoter (108 bp) showed weak activity in E-cad- lines and hybrids, but strong activity in E-cad+ lines.
- E-cadherin expression was not restored by demethylating or deacetylase inhibiting agents.
Conclusions:
- Dominant repression of trans-acting pathways regulating E-cadherin transcription likely underlies E-cadherin loss in some breast cancers.
- Epigenetic modifications (demethylation, histone deacetylation) do not appear to be the primary cause of E-cadherin inactivation in these models.
- Findings highlight the importance of regulatory pathways in E-cadherin function and cancer progression.