C-Src modulates estrogen-induced stress and apoptosis in estrogen-deprived breast cancer cells

Ping Fan, Obi L. Griffith, Fadeke A. Agboke, Pavana Anur, Xiaojun Zou, Russell E. McDaniel, Karen Creswell, Sung Hoon Kim, John A. Katzenellenbogen, Joe W. Gray, V. Craig Jordan

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51 Scopus citations

Abstract

The emergence of anti-estrogen resistance in breast cancer is an important clinical phenomenon affecting long-term survival in this disease. Identifying factors that convey cell survival in this setting may guide improvements in treatment. Estrogen (E2) can induce apoptosis in breast cancer cells that have been selected for survival after E2 deprivation for long periods (MCF-7:5C cells), but the mechanisms underlying E2-induced stress in this setting have not been elucidated. Here, we report that the c-Src kinase functions as a key adapter protein for the estrogen receptor (ER, ESR1) in its activation of stress responses induced by E2 in MCF-7:5C cells. E2 elevated phosphorylation of c-Src, which was blocked by 4-hydroxytamoxifen (4-OHT), suggesting that E2 activated c-Src through the ER. We found that E2 activated the sensors of the unfolded protein response (UPR), IRE1a (ERN1) and PERK kinase (EIF2AK3), the latter of which phosphorylates eukaryotic translation initiation factor-2α (eIF2α). E2 also dramatically increased reactive oxygen species production and upregulated expression of heme oxygenase HO-1 (HMOX1), an indicator of oxidative stress, along with the central energy sensor kinase AMPK (PRKAA2). Pharmacologic or RNA interference-mediated inhibition of c-Src abolished the phosphorylation of eIF2a and AMPK, blocked E2-induced ROS production, and inhibited E2-induced apoptosis. Together, our results establish that c-Src kinase mediates stresses generated by E2 in long-term E2-deprived cells that trigger apoptosis. This work offers a mechanistic rationale for a new approach in the treatment of endocrine-resistant breast cancer.

Original languageEnglish
Pages (from-to)4510-4520
Number of pages11
JournalCancer research
Volume73
Issue number14
DOIs
StatePublished - Jul 15 2013

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    Fan, P., Griffith, O. L., Agboke, F. A., Anur, P., Zou, X., McDaniel, R. E., Creswell, K., Kim, S. H., Katzenellenbogen, J. A., Gray, J. W., & Jordan, V. C. (2013). C-Src modulates estrogen-induced stress and apoptosis in estrogen-deprived breast cancer cells. Cancer research, 73(14), 4510-4520. https://doi.org/10.1158/0008-5472.CAN-12-4152