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.
Highlights
70% of breast tumors express estrogen receptor alpha (ERalpha) [1, 2]
To study the regulation of MitogenActivated Protein Kinase Phosphatases (MKPs) and their effect on Mitogen-Activated Protein Kinases (MAPKs) signaling in tamoxifen sensitivity, we identified a cell line model suitable for expression of exogenous MKP proteins
We show here that treatment with TAM stimulates the expression of MKP-2, but does not have the same effect on MKP-1
Summary
70% of breast tumors express estrogen receptor alpha (ERalpha) [1, 2]. For women who present with ERalpha-positive tumors, first-line therapy involves treatment with tamoxifen. 30-50% of women with metastatic disease will experience temporary remission while being treated with tamoxifen [3, 4] Most of these women will eventually develop recurrent disease that is resistant to tamoxifen treatment. There are many proposed mechanisms of tamoxifen resistance, including, but not limited to, ligand-independent activation of the estrogen receptor [1] and tamoxifen acting as an agonist via crosstalk with other transcription factors [5]. Both of these resistance mechanisms have been connected to the activity of extracellular signal regulated kinases (ERK), one of the Mitogen-Activated Protein Kinases (MAPKs) [1, 5]. Pharmacological inhibition of ERK activity in vitro has been shown to reverse the tamoxifen resistant phenotype in breast [10] and several other cancer types [11, 12]
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