Functional analysis of MKP-1 and MKP-2 in breast cancer tamoxifen sensitivity
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Kelly K. Haagenson1,2, Jessica Wei Zhang2, Zhengfan Xu2, Malathy P.V. Shekhar1,2,3, Gen Sheng Wu1,2,3
1 Department of Oncology, Wayne State University School of Medicine, Detroit, MI
2 Barbara Ann Karmanos Cancer Institute, Detroit, MI
3 Department of Pathology, Wayne State University School of Medicine, Detroit, MI
Gen Sheng Wu, email:
Malathy Shekhar, email: [email protected], email:
Keywords: MKP-1, MKP-2, ERK, tamoxifen sensitivity, breast cancer
Received: January 29, 2014 Accepted: March 11, 2014 Published: March 13, 2014
Increased activation of ERK signaling has been reported in breast cancer models of acquired tamoxifen resistance. Here, we examined the expression of Mitogen-Activated Protein Kinase Phosphatases (MKPs) 1 and 2 following tamoxifen treatment and the effects of MKP-1/MKP-2 overexpression on tamoxifen sensitivity. Treatment of MCF7 breast cancer cells with tamoxifen increased MKP-2, but not MKP-1, protein levels. Overexpression of MKP-1 or MKP-2 inhibited estrogen-induced MCF7 cell proliferation compared to vector controls. MCF7-MKP-2 cells displayed significantly increased sensitivity to tamoxifen as compared to vector control or MCF7-MKP-1 cells. MKP-1 or MKP-2 overexpression eliminated ERK1/2 phosphorylation, suggesting that decreases in estrogen-induced proliferation of MKP-1 and MKP-2 overexpressing cells are due to ERK1/2 dephosphorylation. JNK1/2 activation was not detectable in any of these cells. These data suggest that tamoxifen-induced death of these cells is not dependent upon JNK signaling, but rather that ERK is the major MAPK driving their proliferation. MCF7-TAMR cells express higher levels of MKP-2 mRNA and protein than MCF7 cells. MKP-2 and phospho-ERK1/2 proteins are constitutively expressed in MCF7-TAMR cells, and activated JNK1/2 is not detectable. These data suggest that MKP-2 rather than MKP-1 is tamoxifen-regulated and that the elevated expression of MKP-2 in MCF7-TAMR cells potentially functions to restore tamoxifen sensitivity.
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