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Building Up a High-throughput Screening Platform to Assess the Heterogeneity of HER2 Gene Amplification in Breast Cancers
Published on: December 5, 2017
Co-Treatment with Sulforaphane and Nano-Metformin Molecules Accelerates Apoptosis in HER2+ Breast Cancer Cells by
A Keshandehghan1, S Nikkhah2, H Tahermansouri2
1Department of Stem Cells and Regenerative Medicine, Division of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran.
Abstract:
Breast cancer cell lines MCF-10, MCF-7 and BT-474 expressing various levels of HER2 were examined for their response to treatment with sulforaphane (SLFN), metformin (MTFN), Nano-MTFN or combinations. Direct correlation was found between SLFN effect on cell death and HER2 levels. Bioinformatic studies suggested the possibility of additive co-effects on cell fate by SLFN-MTFN co-treatment. This co-treatment specially with SLFN + Nano-MTFN significantly affected the survival of the cells and killed more BT-474 cells than the other two. Cell sensitivity to SLFN-MTFN combination correlated with HER2 expression levels. RT-PCR showed that parallel with cell death, expression of BCL-2, SRC, WNT1, β-catenin and CD44 are diminished, whereas BAX levels are elevated significantly. Cell co-staining indicated that apoptosis percent correlates with cell death following different treatments. We also found that cell death induced by SLFN-MTFN co-treatment is in direct correlation with HER2 levels and increased cell death correlates directly with BAX levels but inversely with levels of cancer stem cell (CSC) signaling genes and CD44. In conclusion, our data indicate that SLFN and MTFN can reduce cancer cell viability via both collaborative and differential effects and suggest that MTFN increases SLFN effectiveness by targeting common molecules/pathways downstream of HER2 and key for CSC signaling.
Insights
Sulforaphane (SLFN) and metformin (MTFN) combination therapy effectively reduces breast cancer cell viability, particularly in HER2-expressing cells. This synergy enhances cell death by targeting cancer stem cell signaling pathways.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- HER2-positive breast cancer remains a significant clinical challenge.
- Sulforaphane (SLFN) and metformin (MTFN) show individual anti-cancer properties.
- Investigating combination therapies can reveal synergistic effects.
Purpose of the Study:
- To evaluate the combined efficacy of SLFN and MTFN on breast cancer cell lines with varying HER2 levels.
- To elucidate the molecular mechanisms underlying the synergistic effects of SLFN-MTFN co-treatment.
- To determine the correlation between HER2 expression and treatment response.
Main Methods:
- Utilized breast cancer cell lines (MCF-10, MCF-7, BT-474) with differential HER2 expression.
- Administered SLFN, MTFN, Nano-MTFN, and their combinations.
- Performed RT-PCR to analyze gene expression changes (BCL-2, SRC, WNT1, β-catenin, CD44, BAX).
- Assessed apoptosis using cell co-staining.
Main Results:
- SLFN and MTFN co-treatment, especially with Nano-MTFN, significantly reduced cell viability and increased apoptosis.
- Treatment efficacy correlated directly with HER2 expression levels.
- Gene expression analysis revealed decreased BCL-2, SRC, WNT1, β-catenin, and CD44, with increased BAX.
- Cell death was inversely correlated with cancer stem cell (CSC) signaling genes and CD44.
Conclusions:
- SLFN and MTFN exhibit collaborative and differential effects in reducing breast cancer cell viability.
- MTFN enhances SLFN's effectiveness by targeting pathways downstream of HER2 and crucial for CSC signaling.
- The combination therapy holds promise for HER2-positive breast cancers, particularly those with stem cell characteristics.
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