Open Access Dissertation
Date of Award
Gen Sheng Wu
EXPRESSION AND REGULATION OF MAP KINASE PHOSPHATASES 1 and 2 IN BREAST CANCER TAMOXIFEN SENSITIVITY
KELLY K. HAAGENSON
Advisor: Dr. Malathy Shekhar
Co-Advisor: Dr. Gen Sheng Wu
Major: Cancer Biology
Degree: Doctor of Philosophy
The deregulation of cell signaling is a very important component in the development and progression of cancer. One group of signaling molecules that has been implicated in these processes is the Mitogen-Activated Protein Kinase (MAPK) family which consists of three major branches in mammalian cells: ERK, JNK and p38. The activity of these kinases has wide-ranging effects within the cell and must be tightly regulated. This is partially accomplished through the activity of Mitogen-Activated Protein Kinase Phosphatases (MKPs). The MKPs are a family of eleven dual-specificity threonine-tyrosine phosphatases that attenuate MAP Kinase signaling by dephosphorylating them.
Increased ERK signaling has been shown to correlate with poor prognosis in breast cancer patients and is commonly found in tumors that are resistant to tamoxifen treatment. JNK signaling has also been shown to be increased in breast cancer tissue samples. MKP-1 overexpression in breast cancer has been connected with resistance to a number of different chemotherapeutic agents with the underlying mechanism being a decrease in JNK-mediated apoptosis, but no association with tamoxifen response has been previously studied. These observations lead to the hypothesis that MKP-1 overexpression contributes to changes in tamoxifen sensitivity via the inhibition of JNK-mediated apoptosis.
The characterization of MKP-1 following its overexpression in the MCF7 cell line revealed that its expression is not changed after tamoxifen treatment, but that the expression of MKP-2 was increased following treatment with anti-estrogens. Both MKP-1 and MKP-2 decreased cell proliferation in response to estrogen and maintained the tamoxifen sensitivity of MCF7 cells. This decrease in proliferation was attributed to the elimination of ERK phosphorylation, as no JNK activation was observed in these cells. MKP-2 protein expression was shown to be constitutive in MCF7 tamoxifen resistant cells, while MKP-1 expression was not detected. All of these results suggest that MKP-2 expression is upregulated in response to tamoxifen treatment in order to dephosphorylate ERK and slow cell proliferation. In tamoxifen resistant cells, upregulation of MKP-2 expression is most likely an attempt to bring the high levels of ERK activation back down to a more normal level. Its inability to do so is what allows the tamoxifen resistant phenotype to persist.
Haagenson, Kelly, "Expression And Regulation Of Map Kinase Phosphatases 1 And 2 In Breast Cancer Tamoxifen Sensitivity" (2013). Wayne State University Dissertations. 659.