PKCα expression is a marker for breast cancer aggressiveness

BackgroundProtein kinase C (PKC) isoforms are potential targets for breast cancer therapy. This study was designed to evaluate which PKC isoforms might be optimal targets for different breast cancer subtypes.ResultsIn two cohorts of primary breast cancers, PKCα levels correlated to estrogen and progesterone receptor negativity, tumor grade, and proliferative activity, whereas PKCδ and PKCε did not correlate to clinicopathological parameters. Patients with PKCα-positive tumors showed poorer survival than patients with PKCα-negative tumors independently of other factors. Cell line studies demonstrated that PKCα levels are high in MDA-MB-231 and absent in T47D cells which proliferated slower than other cell lines. Furthermore, PKCα silencing reduced proliferation of MDA-MB-231 cells. PKCα inhibition or downregulation also reduced cell migration in vitro.ConclusionsPKCα is a marker for poor prognosis of breast cancer and correlates to and is important for cell functions associated with breast cancer progression.

[1]  Jie Huang,et al.  Protein kinase C-ε protects MCF-7 cells from TNF-mediated cell death by inhibiting Bax translocation , 2007, Apoptosis.

[2]  R. Kiyamova,et al.  Medullary breast carcinoma. , 2008, Experimental oncology.

[3]  R. Schiff,et al.  Upregulation of PKC-δ contributes to antiestrogen resistance in mammary tumor cells , 2005, Oncogene.

[4]  Linda Holmquist Mengelbier,et al.  Hypoxia-inducible factor-2alpha correlates to distant recurrence and poor outcome in invasive breast cancer. , 2008, Cancer research.

[5]  D. Bentrem,et al.  Novel antitumor effect of estradiol in athymic mice injected with a T47D breast cancer cell line overexpressing protein kinase Calpha. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[6]  Xin Lin,et al.  Overexpression of PKCalpha is required to impart estradiol inhibition and tamoxifen-resistance in a T47D human breast cancer tumor model. , 2005, Carcinogenesis.

[7]  G. Landberg,et al.  Deregulation of cyclin E and D1 in breast cancer is associated with inactivation of the retinoblastoma protein , 1997, Oncogene.

[8]  P. Parker,et al.  PKC alpha protein but not kinase activity is critical for glioma cell proliferation and survival , 2008, International journal of cancer.

[9]  A. Raghunath,et al.  The catalytic domain limits the translocation of protein kinase C α in response to increases in Ca 2 u and diacylglycerol , 2022 .

[10]  S. Rotenberg,et al.  Phosphorylation of α6-Tubulin by Protein Kinase Cα Activates Motility of Human Breast Cells* , 2009, The Journal of Biological Chemistry.

[11]  S. Merajver,et al.  Protein kinase C epsilon is a predictive biomarker of aggressive breast cancer and a validated target for RNA interference anticancer therapy. , 2005, Cancer research.

[12]  J. Stenvang,et al.  Protein Kinase C α is a marker for antiestrogen resistance and is involved in the growth of tamoxifen resistant human breast cancer cells , 2007, Breast Cancer Research and Treatment.

[13]  Timothy W. Gant,et al.  Regulation of MDR1 promoter activity in human breast carcinoma cells by protein kinase C isozymes α and Θ , 2001 .

[14]  D. Roychowdhury,et al.  Antisense therapy directed to protein kinase C-alpha (Affinitak, LY900003/ISIS 3521): potential role in breast cancer. , 2003, Seminars in oncology.

[15]  P. Bastiaens,et al.  PKCα regulates β1 integrin‐dependent cell motility through association and control of integrin traffic , 1999 .

[16]  I. Ellis,et al.  Protein kinase C isoform expression as a predictor of disease outcome on endocrine therapy in breast cancer , 2007, Journal of Clinical Pathology.

[17]  K. Jirström,et al.  Oestrogen receptors α and β show different associations to clinicopathological parameters and their co-expression might predict a better response to endocrine treatment in breast cancer , 2007, Journal of Clinical Pathology.

[18]  S. Kiley,et al.  Protein Kinase C δ Involvement in Mammary Tumor Cell Metastasis , 1999 .

[19]  D. Fabbro,et al.  Selective regulation of expression of protein kinase C (PKC) isoenzymes in multidrug-resistant MCF-7 cells. Functional significance of enhanced expression of PKC alpha. , 1993, The Journal of biological chemistry.

[20]  J. Winstanley,et al.  Protein kinase C alpha expression in normal breast, ductal carcinoma in situ and invasive ductal carcinoma. , 2004, European journal of cancer.

[21]  A. Raghunath,et al.  The catalytic domain limits the translocation of protein kinase C alpha in response to increases in Ca2+ and diacylglycerol. , 2003, The Biochemical journal.

[22]  J. Stenvang,et al.  Breast cancer cells with acquired antiestrogen resistance are sensitized to cisplatin-induced cell death , 2007, Molecular Cancer Therapeutics.

[23]  J. Lennartsson,et al.  Protein Kinase Cδ Supports Survival of MDA-MB-231 Breast Cancer Cells by Suppressing the ERK1/2 Pathway* , 2009, The Journal of Biological Chemistry.

[24]  S. Rotenberg,et al.  Immunohistochemical Analysis of Advanced Human Breast Carcinomas Reveals Downregulation of Protein Kinase Cα , 2004, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[25]  Y. Hannun,et al.  A novel role for protein kinase Cδ‐mediated phosphorylation of acid sphingomyelinase in UV light‐induced mitochondrial injury , 2008, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[26]  G. Landberg,et al.  Cyclin E overexpression, a negative prognostic factor in breast cancer with strong correlation to oestrogen receptor status. , 1996, British Journal of Cancer.

[27]  M. Kazanietz,et al.  Protein kinase C δ enhances proliferation and survival of murine mammary cells , 2007 .

[28]  V. Jordan,et al.  Stable transfection of protein kinase C alpha cDNA in hormone-dependent breast cancer cell lines , 2000, British Journal of Cancer.

[29]  William E. Hughes,et al.  Site-Directed Perturbation of Protein Kinase C- Integrin Interaction Blocks Carcinoma Cell Chemotaxis , 2002, Molecular and Cellular Biology.

[30]  A. Basu,et al.  Downregulation of Bid is associated with PKCɛ-mediated TRAIL resistance , 2007, Cell Death and Differentiation.

[31]  R. Tibshirani,et al.  Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[32]  P. Parker,et al.  MCF-7 breast cancer cells transfected with protein kinase C-alpha exhibit altered expression of other protein kinase C isoforms and display a more aggressive neoplastic phenotype. , 1995, The Journal of clinical investigation.

[33]  L. Miraglia,et al.  Protein kinase C delta is a prosurvival factor in human breast tumor cell lines. , 2003, Molecular cancer therapeutics.

[34]  A. Newton,et al.  Protein kinase C: structural and spatial regulation by phosphorylation, cofactors, and macromolecular interactions. , 2001, Chemical reviews.

[35]  P. Jurasz,et al.  Protein Kinase Cδ Mediates Platelet-Induced Breast Cancer Cell Invasion , 2006, Journal of Pharmacology and Experimental Therapeutics.

[36]  J. Rosen,et al.  Modelling breast cancer: one size does not fit all , 2007, Nature Reviews Cancer.

[37]  S. Kiley,et al.  Increased protein kinase Cδ in mammary tumor cells: relationship to transformation and metastatic progression , 1999, Oncogene.

[38]  T. Gant,et al.  Regulation of MDR1 promoter activity in human breast carcinoma cells by protein kinase C isozymes alpha and theta. , 2001, European journal of biochemistry.

[39]  M. Morrow,et al.  Elevated protein kinase C alpha expression may be predictive of tamoxifen treatment failure , 2003, British Journal of Cancer.

[40]  C. Larsson,et al.  PKCε, Via its Regulatory Domain and Independently of its Catalytic Domain, Induces Neurite-like Processes in Neuroblastoma Cells , 1999, The Journal of cell biology.

[41]  G. Landberg,et al.  Telomerase activity in relation to p53 status and clinico‐pathological parameters in breast cancer , 1998, International journal of cancer.

[42]  Michael C. Ostrowski,et al.  ERK phosphorylation is linked to VEGFR2 expression and Ets-2 phosphorylation in breast cancer and is associated with tamoxifen treatment resistance and small tumours with good prognosis , 2005, Oncogene.

[43]  J. Chen,et al.  Phorbol esters induce death in MCF-7 breast cancer cells with altered expression of protein kinase C isoforms. Role for p53-independent induction of gadd-45 in initiating death. , 1995, The Journal of clinical investigation.