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Suppressing Src-Mediated EGFR Signaling by Sustained Calcium Supply Targeting Triple-Negative Breast Cancer
Keun-Yeong Jeong1, Seon Young Park1, Min Hee Park1
1Gachon Institute of Pharmaceutical Science, Gachon University, Incheon 21936, Republic of Korea.
Abstract:
Src is emerging as a promising target in triple-negative breast cancer (TNBC) treatment because it activates survival signaling linked to the epidermal growth factor receptor. In this study, the effect of calcium supply on Src degradation was investigated to confirm underlying mechanisms and anticancer effects targeting TNBC. MDA-MB-231 cells, the TNBC cell line, were used. Calcium supply was feasible through lactate calcium salt (CaLac), and the applicable calcium concentration was decided by changes in the viability with different doses of CaLac. Expression of signaling molecules mediated by calcium-dependent Src degradation was observed by Western blot analysis and immunocytochemistry, and the recovery of the signaling molecules was confirmed following calpeptin treatment. The anticancer effect was investigated in the xenograft animal model. Significant suppression of Src was induced by calcium supply, followed by a successive decrease in the expression of epithelial growth factor receptor, RAS, extracellular signal-regulated kinase, and nuclear factor kappa B. Then, the suppression of cyclooxygenase-2 contributed to a significant deactivation of the prostaglandin E2 receptors. These results suggest that calcium supply has the potential to reduce the risk of TNBC. However, as this study is at an early stage to determine clinical applicability, close consideration is needed.
Insights
Calcium supplementation effectively degrades Src, a key protein in triple-negative breast cancer (TNBC) survival signaling. This approach shows potential for TNBC treatment by inhibiting critical cancer pathways.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Src kinase is a promising therapeutic target in triple-negative breast cancer (TNBC).
- Src activation is linked to epidermal growth factor receptor (EGFR) signaling, promoting cancer cell survival.
- Understanding mechanisms of Src regulation is crucial for developing novel TNBC treatments.
Purpose of the Study:
- To investigate the effect of calcium supply on Src degradation in TNBC.
- To elucidate the underlying molecular mechanisms of calcium-mediated Src inhibition.
- To evaluate the anticancer effects of calcium supplementation in a TNBC model.
Main Methods:
- Utilized MDA-MB-231 TNBC cell line and a xenograft animal model.
- Administered calcium via lactate calcium salt (CaLac) to determine optimal concentrations.
- Analyzed signaling molecule expression (Src, EGFR, RAS, ERK, NF-κB, COX-2) using Western blot and immunocytochemistry.
- Assessed effects on prostaglandin E2 receptor signaling.
Main Results:
- Calcium supply significantly suppressed Src expression in TNBC cells.
- This led to decreased expression of downstream signaling molecules including EGFR, RAS, ERK, and NF-κB.
- Suppression of cyclooxygenase-2 (COX-2) resulted in deactivation of prostaglandin E2 receptors.
- Calcium treatment demonstrated anticancer effects in a TNBC xenograft model.
Conclusions:
- Calcium supply effectively induces Src degradation, impacting multiple pro-survival pathways in TNBC.
- This study suggests calcium supplementation as a potential therapeutic strategy for TNBC.
- Further research is required to determine the clinical applicability of calcium for TNBC treatment.
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