Approximately 15-20% of breast cancers have a triple negative phenotype (negative for ER and PR expression and lack ErbB2 overexpression) that correlates with aggressive cancer and limited treatment options. We have developed an in vivo screen for defining the role of specific kinases in tumorigenesis and metastasis of breast cancer cells. Triple negative and triple positive breast cancer lines were used for shRNA-mediated knock down of specific kinases. The genetically altered lines (expressing luciferase in addition to specific shRNA gene knockdown) are injected into the mammary fat pad of female SCID mice. Tumor growrth and vascularization is monitored longitudinally over an 8 week period using a micro-probe ultrasound system. Metastasis is monitored by bioluminescence imaging. The assay provides an in vivo screen for analysis of proteins that control the growth, vascularization and metastasis of breast tumors. MAPSKs are the first tier of kinases regulating the MAP kinase signaling pathways that lead to the activation of the MAPKs ERK1/2, p38, JNK and ERK5. MAPSKs control expression of genes important for regulating the cell cycle, cytokine and protease expression and apoptosis. In a screen of 9 MAPSKs, MEKK2 was identified as a key regulator of metastasis using MDA-MB-2S1 (triple negative basal) and BT474 (triple positive luminal) breast adenocarcinoma cells in the in vivo tumorigenesis assay. MEKK2 is a MAPSK that regulates the activation of the JNK and ERK5 pathways via activation of MKK7 and MEK5. We have shown that MEKK2 expression is required for EGFR (ErbBI) and ErbB2/Neu activation of ERK5 in MDA-MB-2S1 and BT474 cells, respectively. Our hypothesis is that the MAPSK MEKK2 functions as a critical signaling node within the cell signaling network stimulating tumor growth and metastasis in response to ErbB and possibly other tyrosine kinases. The goal of this proposal is to genetically define the role of MEKK2 in triple negative breast cancer tumor grovirth and metastasis and to develop a MEKK2 small molecule inhibitor.
Specific aim 1 involves defining the role of MEKK2-MEK5-ERK5 signaling in tumorigenesis and metastasis of triple negative breast cancer cells using the in vivo xenograft assay.
In specific aim 2, we propose to elucidate the mechanism by which MEKK2 gets activated by ErbBI/2 using MEKK2 mutants in biochemical and cell-based activation assays.
In specific aim S, a small molecule biochemical screen will be developed to identify compounds that specifically inhibit MEKK2 kinase activity. MEKK2 inhibitors will be tested for MAPK pathway specificity in cell-based assays and profiled for specificity against the kinome. In future studies, these MEKK2 inhibitors will be tested for anti-tumor efficacy in genetically engineered mouse models (GEMMs) of breast cancer.
|DeBono, Nathan L; Robinson, Whitney R; Lund, Jennifer L et al. (2017) Race, Menopausal Hormone Therapy, and Invasive Breast Cancer in the Carolina Breast Cancer Study. J Womens Health (Larchmt) :|
|Bruno, Robert D; Fleming, Jodie M; George, Andrea L et al. (2017) Mammary extracellular matrix directs differentiation of testicular and embryonic stem cells to form functional mammary glands in vivo. Sci Rep 7:40196|
|Reaves, Denise K; Hoadley, Katherine A; Fagan-Solis, Katerina D et al. (2017) Nuclear Localized LSR: A Novel Regulator of Breast Cancer Behavior and Tumorigenesis. Mol Cancer Res 15:165-178|
|Huo, Dezheng; Hu, Hai; Rhie, Suhn K et al. (2017) Comparison of Breast Cancer Molecular Features and Survival by African and European Ancestry in The Cancer Genome Atlas. JAMA Oncol 3:1654-1662|
|Williams, Lindsay A; Olshan, Andrew F; Hong, Chi-Chen et al. (2017) Alcohol Intake and Breast Cancer Risk in African American Women from the AMBER Consortium. Cancer Epidemiol Biomarkers Prev 26:787-794|
|Chollet-Hinton, Lynn; Anders, Carey K; Tse, Chiu-Kit et al. (2016) Breast cancer biologic and etiologic heterogeneity by young age and menopausal status in the Carolina Breast Cancer Study: a case-control study. Breast Cancer Res 18:79|
|Robinson, Whitney R; Nichols, Hazel B; Tse, Chiu Kit et al. (2016) Associations of Premenopausal Hysterectomy and Oophorectomy With Breast Cancer Among Black and White Women: The Carolina Breast Cancer Study, 1993-2001. Am J Epidemiol 184:388-99|
|Liu, Yongjing; Xiong, Zhaohui; Beasley, Andrea et al. (2016) Personalized and targeted therapy of esophageal squamous cell carcinoma: an update. Ann N Y Acad Sci 1381:66-73|
|Xiong, Zhaohui; He, Jingxi; Chen, Xiaoxin Luke (2016) New strategies in esophageal carcinoma: promises and problems. J Thorac Dis 8:E1501-E1504|
|Butler, Eboneé N; Tse, Chiu-Kit; Bell, Mary Elizabeth et al. (2016) Active smoking and risk of Luminal and Basal-like breast cancer subtypes in the Carolina Breast Cancer Study. Cancer Causes Control 27:775-86|
Showing the most recent 10 out of 32 publications