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Review
. 2010 Mar;29(1):143-9.
doi: 10.1007/s10555-010-9208-5.

The role of MAP kinases and MAP kinase phosphatase-1 in resistance to breast cancer treatment

Kelly K Haagenson  1 , Gen Sheng Wu
Affiliations
Review

The role of MAP kinases and MAP kinase phosphatase-1 in resistance to breast cancer treatment

Kelly K Haagenson et al. Cancer Metastasis Rev. 2010 Mar.

Abstract

Chemotherapy resistance is an important problem often encountered during the course of breast cancer treatment. In order to design rational and efficacious therapies, the molecular mechanisms used by cells to develop resistance must be investigated. One mechanism employed by cancer cells is to alter cell signaling. This review examines the role of mitogen-activated protein kinases (MAPKs) and their endogenous negative regulators, mitogen-activated protein kinase phosphatases (MKPs), in chemotherapy resistance in breast cancer. MAPK signaling is activated in response to both growth factors and cellular stress. MKPs dephosphorylate MAPKs and are part of the dual-specificity family of phosphatases. MAPKs have been shown to be involved in resistance to tamoxifen, and MKPs have been linked to resistance to treatment with doxorubicin, mechlorethamine, paclitaxel, proteasome inhibitors, and oxidative-stress-induced cell death in breast cancer. The role of MKPs in tamoxifen resistance and the elucidation of the mechanisms involved with resistance to standard chemotherapy agents need to be investigated further. Growing evidence suggests that modulating MKP-1 activity could be a viable option to make breast cancer chemotherapy more effective.

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Figures

Fig. 1
Fig. 1
MAP kinase signaling. The three branches of the MAP kinase signaling family in mammalian cells are activated by stimuli at the cell surface. MAP kinase kinase kinases relay the signal to MAP kinase kinases, which activate ERK, JNK, and p38. The phosphorylation of their respective targets completes the cascade. MAP kinase phosphatases are endogenous negative regulators of MAP kinases. MKPs attenuate the signal by dephosphorylation and prevent MAPKs from carrying out their cellular functions
Fig. 2
Fig. 2
MKP-1 and chemoresistance. Overexpression of MKP-1 plays a role in the development of resistance to chemotherapy in breast, lung, and ovarian cancers. In breast cancer, decreased JNK and p38 activity contributes to resistance to oxidative-stress-induced death. Treatment with proteasome inhibitors increases ERK and decreases JNK activity, leading to proteasome inhibitor resistance because of decreased levels of apoptosis. Activation of the glucocorticoid receptor increases MKP-1 mRNA and causes decreased JNK and ERK activity, which factors in to paclitaxel resistance. Cisplatin resistance in lung and ovarian cancer is caused in part by decreased JNK activity
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