Inhibition of c-Src blocks oestrogen-induced apoptosis and restores oestrogen-stimulated growth in long-term oestrogen-deprived breast cancer cells

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• 作者：Ping Fan ; Fadeke A. Agboke ; Russell E. McDaniel ; Elizabeth E. Sweeney ; Xiaojun Zou ; Karen Creswell ; V. Craig Jordan
• 关键词：c-Src ; Oestrogen ; Apoptosis ; Epithelial&ndash ; mesenchymal transition ; Breast cancer
• 刊名：European Journal of Cancer
• 出版年：January, 2014
• 年：2014
• 卷：50
• 期：2
• 页码：457-468
• 全文大小：1960 K

文摘

Purpose

Our publications demonstrate that physiological concentrations of oestrogen (E₂) induce endoplasmic reticulum and oxidative stress which finally result in apoptosis in E₂-deprived breast cancer cells, MCF-7:5C. c-Src is involved in the process of E₂-induced stress. To mimic the clinical administration of c-Src inhibitors, we treated cells with either E₂, a c-Src inhibitor PP2, or the combination for 8 weeks to further explore the apoptotic potential of the c-Src inhibitor and E₂ on MCF-7:5C cells.

Methods

Protein levels of receptors and signalling pathways were examined by immunoblotting. Expression of mRNA was detected through real-time polymerase chain reaction (PCR). Cell cycles were analysed by flow cytometry.

Results

Long-term treatment with PP2 alone or E₂ alone decreased cell growth. In contrast, a combination of PP2 and E₂ blocked apoptosis and the resulting cell line (MCF-7:PF) was unique, as they grew vigorously in culture with physiological levels of E₂, which could be blocked by the pure antioestrogen ICI182,780. One major change was that PP2 collaborated with E₂ to increase the level of insulin-like growth factor-1 receptor beta (IGF-1R尾). Blockade of IGF-1R尾 completely abolished E₂-stimulated growth in MCF-7:PF cells. Furthermore, combination treatment up-regulated transcription factors, Twist1 and Snail, and repressed E-cadherin expression which made MCF-7:PF cells display a characteristic phenotype of epithelial-mesenchymal transition (EMT).

Conclusions

These data illustrate the role of the c-Src inhibitor to block E₂-induced apoptosis and enhance E₂-stimulated growth. Caution must be exercised when considering c-Src inhibitors in clinical trials following the development of acquired resistance to aromatase inhibitors, especially in the presence of the patient鈥檚 own oestrogen.