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Identification of a GαGβγ, AKT and PKCα signalome associated with invasive growth in two genetic models of human breast cancer cell epithelial-to-mesenchyinal transition

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Abstract
The epithelial-to-mesenchymal transition (EMT) confers an aggressive subtype associated with chemotherapy resistance in epithelial cancers. However, the mechanisms underlying the EMT and its associated signaling dysfunctions are still poorly understood. In two genetic models of MCF-7 breast cancer cells induced to EMT by WISP-2 silencing and Snail transformation, we investigated the status of several signaling elements downstream of G-protein receptors (GPR) and their functional roles in the invasive growth potential. We report that the E-cadherin repressors Slug, Zeb1/2 and Twist are overexpressed in these EMT cells characterized by a triple negative phenotype (loss of estrogen ER alpha and progesterone PRA/PRB receptors, no HER2 amplification), combined with loss of the alternative GPR30 estrogen receptor and induction of the invasive growth in collagen type I gels. Ectopic Snail expression suppressed WISP-2 transcripts and downregulated WISP-2 gene promoter expression in transfected cells. Accordingly, WISP-2 transcripts and Wisp-2 protein were depleted in these two convergent models of BC cell EMT. The EMT caused dominance of several proinvasive pathways downstream of GPR, including G alpha G beta gamma subunits, PKC alpha, AKT and c-Jun induction, constitutive activation of the actin-remodeling GTPase Rac1, coupled with growth responses (more cells at S and G2/M phases of the cell cycle), in line with inhibition of the p27(kip1)/cyclin-dependent kinase CDK3 cascade. RNA interference or selective inhibitors targeting G alpha G beta gamma subunits (BIM-46187, gallein), PKC alpha (Go6976, MT477, sh-RNAs) and PI3K-AKT (wortmannin:, alleviated the invasive phenotype. In contrast, MCF-7 cells in EMT showed signaling independence to inhibitors of HER family tyrosine kinases and the mitogen- and stress-activated protein kinases. Our study suggests that the signaling protagonists G alpha G beta gamma, PKC alpha and PI3K-AKT are promising candidates as predictive molecular biomarkers and therapeutic targets in the management of clinical BC in EMT.
Keywords
WISP-2, Snail, Rac1 GTPase, GPR30, short-herpin RNAs, p27, protein kinase C-alpha, targeted-therapy, PROTEIN-COUPLED RECEPTORS, prognosis, HER family, DOWN-REGULATION, ESTROGEN-RECEPTOR, METASTASIS, DRUG DISCOVERY, EXPRESSION, ACTIVATION, P27(KIP1), PATHWAY, CYCLE

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MLA
Ouelaa-Benslama, Radia, Olivier De Wever, An Hendrix, et al. “Identification of a GαGβγ, AKT and PKCα Signalome Associated with Invasive Growth in Two Genetic Models of Human Breast Cancer Cell Epithelial-to-mesenchyinal Transition.” INTERNATIONAL JOURNAL OF ONCOLOGY 41.1 (2012): 189–200. Print.
APA
Ouelaa-Benslama, R., De Wever, O., Hendrix, A., Sabbah, M., Lambein, K., Land, D., Prévost, G., et al. (2012). Identification of a GαGβγ, AKT and PKCα signalome associated with invasive growth in two genetic models of human breast cancer cell epithelial-to-mesenchyinal transition. INTERNATIONAL JOURNAL OF ONCOLOGY, 41(1), 189–200.
Chicago author-date
Ouelaa-Benslama, Radia, Olivier De Wever, An Hendrix, Michèle Sabbah, Kathleen Lambein, David Land, Grégoire Prévost, et al. 2012. “Identification of a GαGβγ, AKT and PKCα Signalome Associated with Invasive Growth in Two Genetic Models of Human Breast Cancer Cell Epithelial-to-mesenchyinal Transition.” International Journal of Oncology 41 (1): 189–200.
Chicago author-date (all authors)
Ouelaa-Benslama, Radia, Olivier De Wever, An Hendrix, Michèle Sabbah, Kathleen Lambein, David Land, Grégoire Prévost, Marc Bracke, Mien-Chie Hung, Annette K Larsen, Shahin Emami, and Christian Gespach. 2012. “Identification of a GαGβγ, AKT and PKCα Signalome Associated with Invasive Growth in Two Genetic Models of Human Breast Cancer Cell Epithelial-to-mesenchyinal Transition.” International Journal of Oncology 41 (1): 189–200.
Vancouver
1.
Ouelaa-Benslama R, De Wever O, Hendrix A, Sabbah M, Lambein K, Land D, et al. Identification of a GαGβγ, AKT and PKCα signalome associated with invasive growth in two genetic models of human breast cancer cell epithelial-to-mesenchyinal transition. INTERNATIONAL JOURNAL OF ONCOLOGY. 2012;41(1):189–200.
IEEE
[1]
R. Ouelaa-Benslama et al., “Identification of a GαGβγ, AKT and PKCα signalome associated with invasive growth in two genetic models of human breast cancer cell epithelial-to-mesenchyinal transition,” INTERNATIONAL JOURNAL OF ONCOLOGY, vol. 41, no. 1, pp. 189–200, 2012.
@article{2941298,
  abstract     = {The epithelial-to-mesenchymal transition (EMT) confers an aggressive subtype associated with chemotherapy resistance in epithelial cancers. However, the mechanisms underlying the EMT and its associated signaling dysfunctions are still poorly understood. In two genetic models of MCF-7 breast cancer cells induced to EMT by WISP-2 silencing and Snail transformation, we investigated the status of several signaling elements downstream of G-protein receptors (GPR) and their functional roles in the invasive growth potential. We report that the E-cadherin repressors Slug, Zeb1/2 and Twist are overexpressed in these EMT cells characterized by a triple negative phenotype (loss of estrogen ER alpha and progesterone PRA/PRB receptors, no HER2 amplification), combined with loss of the alternative GPR30 estrogen receptor and induction of the invasive growth in collagen type I gels. Ectopic Snail expression suppressed WISP-2 transcripts and downregulated WISP-2 gene promoter expression in transfected cells. Accordingly, WISP-2 transcripts and Wisp-2 protein were depleted in these two convergent models of BC cell EMT. The EMT caused dominance of several proinvasive pathways downstream of GPR, including G alpha G beta gamma subunits, PKC alpha, AKT and c-Jun induction, constitutive activation of the actin-remodeling GTPase Rac1, coupled with growth responses (more cells at S and G2/M phases of the cell cycle), in line with inhibition of the p27(kip1)/cyclin-dependent kinase CDK3 cascade. RNA interference or selective inhibitors targeting G alpha G beta gamma subunits (BIM-46187, gallein), PKC alpha (Go6976, MT477, sh-RNAs) and PI3K-AKT (wortmannin:, alleviated the invasive phenotype. In contrast, MCF-7 cells in EMT showed signaling independence to inhibitors of HER family tyrosine kinases and the mitogen- and stress-activated protein kinases. Our study suggests that the signaling protagonists G alpha G beta gamma, PKC alpha and PI3K-AKT are promising candidates as predictive molecular biomarkers and therapeutic targets in the management of clinical BC in EMT.},
  author       = {Ouelaa-Benslama, Radia and De Wever, Olivier and Hendrix, An and Sabbah, Michèle and Lambein, Kathleen and Land, David and Prévost, Grégoire and Bracke, Marc and Hung, Mien-Chie and Larsen, Annette K and Emami, Shahin and Gespach, Christian},
  issn         = {1019-6439},
  journal      = {INTERNATIONAL JOURNAL OF ONCOLOGY},
  keywords     = {WISP-2,Snail,Rac1 GTPase,GPR30,short-herpin RNAs,p27,protein kinase C-alpha,targeted-therapy,PROTEIN-COUPLED RECEPTORS,prognosis,HER family,DOWN-REGULATION,ESTROGEN-RECEPTOR,METASTASIS,DRUG DISCOVERY,EXPRESSION,ACTIVATION,P27(KIP1),PATHWAY,CYCLE},
  language     = {eng},
  number       = {1},
  pages        = {189--200},
  title        = {Identification of a GαGβγ, AKT and PKCα signalome associated with invasive growth in two genetic models of human breast cancer cell epithelial-to-mesenchyinal transition},
  url          = {http://dx.doi.org/10.3892/ijo.2012.1457},
  volume       = {41},
  year         = {2012},
}

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