TY - JOUR
T1 - Inhibition of c-Src blocks oestrogen-induced apoptosis and restores oestrogen-stimulated growth in long-term oestrogen-deprived breast cancer cells
AU - Fan, Ping
AU - Agboke, Fadeke A.
AU - McDaniel, Russell E.
AU - Sweeney, Elizabeth E.
AU - Zou, Xiaojun
AU - Creswell, Karen
AU - Jordan, V. Craig
N1 - Funding Information:
V.C.J. is supported by the Department of Defense Breast Program under Award Number W81XWH-06-1-0590 Center of Excellence; subcontract under the SU2C (AACR) Grant Number SU2C-AACR-DT0409; the Susan G Komen For The Cure Foundation under Award Number SAC100009; GHUCCTS CTSA (Grant # UL1RR031975) and the Lombardi Comprehensive Cancer Center Support Grant (CCSG) Core Grant NIH P30 CA051008. We thank Peter Johnson for helping take cell images in the Microscopy and Imaging Shared Resource of the Georgetown University.
Funding Information:
Ping Fan, Fadeke A. Agboke, Russell E. McDaniel and Elizabeth E. Sweeney’s salaries, as well as laboratory supplies supported by the following: the Department of Defense Breast Program under Award Number W81XWH-06-1-0590 Center of Excellence (V.C.J.); subcontract under the SU2C (AACR) Grant Number SU2C-AACR-DT0409 (V.C.J.); the Susan G. Komen for the Cure Foundation under Award Number SAC 100009 (V.C.J.) and the Lombardi Comprehensive Cancer Center Support Grant (CCSG) Core Grant NIH P30 CA051008 (V.C.J.).
PY - 2014/1
Y1 - 2014/1
N2 - 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-1Rβ). Blockade of IGF-1Rβ 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's own oestrogen.
AB - 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-1Rβ). Blockade of IGF-1Rβ 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's own oestrogen.
KW - Apoptosis
KW - Breast cancer
KW - Epithelial-mesenchymal transition
KW - Oestrogen
KW - c-Src
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UR - http://www.scopus.com/inward/citedby.url?scp=84891828889&partnerID=8YFLogxK
U2 - 10.1016/j.ejca.2013.10.001
DO - 10.1016/j.ejca.2013.10.001
M3 - Article
C2 - 24183378
AN - SCOPUS:84891828889
SN - 0959-8049
VL - 50
SP - 457
EP - 468
JO - European Journal of Cancer
JF - European Journal of Cancer
IS - 2
ER -