Snail induces dormancy in disseminated luminal type A breast cancer through Src inhibition
Chun-Te Ho1, Shih-Pei Lin2, Ling-Ming Tseng3,4
1Integrative Stem Cell Center, Department of Orthopaedics, China Medical University Hospital Taichung 404, Taiwan.
Abstract:
Breast cancer includes biologically distinct subtypes, and the time between rise in distant metastases and overall survival for the subtypes are different. The mechanisms involved in these differences in tumor metastasis remain to be elucidated. Here, we demonstrated that, luminal type A breast cancer cells, such as MCF7 and T47D, when overexpressed with active mutant form of Snail (6SA-Snail) increased in the expression of EMT markers such as Vimentin, N-cadherin and Fibronectin but decreased in the expression of E-cadherin, compared to control vectors or wild type Snail. Moreover, this mutant increased in migration and invasion ability, while decreased in the capacity to survive and form spheres in tumor spheroid medium. Luciferase reporter assay and chromatin immunoprecipitation followed by quantitative PCR (ChIP-qPCR) analysis revealed that Snail downregulated Src by binding to the E-box of Src promoter. Human luminal type A breast cancer specimens showed an inverse correlation between Vimentin and Src expression. Most importantly, downregulation of Src by Snail was not found in breast cancer cell types other than luminal type A. Therefore, elucidation of the differences in signaling pathways involved in controlling migration, invasion and colonization may have a therapeutically beneficial effect on breast cancer treatment.
Insights
The Snail protein in luminal A breast cancer promotes metastasis by increasing cell migration and invasion while decreasing survival. This occurs through downregulating Src, a mechanism specific to this subtype.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Breast cancer comprises distinct subtypes with varying metastatic potential and survival rates.
- The molecular mechanisms driving these differences in tumor metastasis are not fully understood.
Purpose of the Study:
- To investigate the role of the Snail protein in luminal A breast cancer metastasis.
- To elucidate the signaling pathways involved in Snail-mediated changes in cell behavior and identify potential therapeutic targets.
Main Methods:
- Overexpression of a mutant Snail form (6SA-Snail) in luminal A breast cancer cell lines (MCF7, T47D).
- Analysis of epithelial-mesenchymal transition (EMT) markers, cell migration, invasion, survival, and sphere formation.
- Luciferase reporter assays and ChIP-qPCR to determine Snail's interaction with the Src promoter.
- Correlation analysis of Vimentin and Src expression in human breast cancer specimens.
Main Results:
- 6SA-Snail overexpression increased EMT markers (Vimentin, N-cadherin, Fibronectin) and enhanced migration/invasion.
- 6SA-Snail decreased cell survival and sphere formation capacity.
- Snail directly downregulated Src expression by binding to its promoter, a mechanism observed only in luminal A cells.
- An inverse correlation between Vimentin and Src expression was found in human luminal A breast cancer.
Conclusions:
- Snail plays a critical role in promoting metastasis in luminal A breast cancer by modulating EMT and downregulating Src.
- The specific downregulation of Src by Snail in luminal A subtype suggests a targeted therapeutic strategy.
- Understanding subtype-specific signaling pathways is crucial for developing effective breast cancer treatments.
