title: Functional analysis of MKP-1 and MKP-2 in breast cancer tamoxifen sensitivity.
abstract: 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.
authors.affiliation: Department of Oncology, Wayne State University School of Medicine, Detroit, MI.
authors.forename: Kelly K
authors.initials: KK
authors.lastname: Haagenson
authors.forename: Jessica Wei
authors.initials: JW
authors.lastname: Zhang
authors.forename: Zhengfan
authors.initials: Z
authors.lastname: Xu
authors.forename: Malathy P V
authors.initials: MP
authors.lastname: Shekhar
authors.forename: Gen Sheng
authors.initials: GS
authors.lastname: Wu
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism*; D054637:Dual-Specificity Phosphatases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000235:genetics / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen; D054639:Mitogen-Activated Protein Kinase Phosphatases; C517019:DUSP1 protein, human; C490583:DUSP4 protein, human; D054638:Dual Specificity Phosphatase 1; D054637:Dual-Specificity Phosphatases