Functional analysis of MKP-1 and MKP-2 in breast cancer tamoxifen sensitivity

• Published in: Oncotarget Vol. 5; no. 4; pp. 1101 - 1115
• Main Authors: Haagenson, Kelly K, Zhang, Jessica Wei, Xu, Zhengfan, Shekhar, Malathy P V, Wu, Gen Sheng
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 28.02.2014
• Subjects: Antineoplastic Agents, Hormonal - pharmacology; Breast Neoplasms - drug therapy; Breast Neoplasms - enzymology; Dual Specificity Phosphatase 1 - metabolism; Dual-Specificity Phosphatases - genetics; Dual-Specificity Phosphatases - metabolism; Female; Humans; Mitogen-Activated Protein Kinase Phosphatases - genetics; Mitogen-Activated Protein Kinase Phosphatases - metabolism; Research Paper; Tamoxifen - pharmacology
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.1795

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.