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Protein Kinase C Is a Predictive Biomarker of Aggressive Breast Cancer and a Validated Target for RNA Interference Anticancer Therapy

¹ Department of Internal Medicine, Division of Hematology and Oncology, Departments of ² Pathology, ³ Surgery, and ⁴ Otolaryngology, ⁵ Biostatistics Core of the Comprehensive Cancer Center, and ⁶ Comprehensive Cancer Center, University of Michigan Health System, Ann Arbor, Michigan

Requests for reprints: Quintin Pan, Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan Medical School, 1500 East Medical Center Drive, Ann Arbor, MI 48109. Phone: 734-647-3408; Fax: 734-615-2719; E-mail: qpan{at}med.umich.edu.

Tumor metastasis is the major cause of morbidity and mortality in patients with breast cancer. It is critical to identify metastasis enabling genes and understand how they are responsible for inducing specific aspects of the metastatic phenotype to allow for improved clinical detection and management. Protein kinase C (PKC), a member of a family of serine/threonine protein kinases, is a transforming oncogene that has been reported to be involved in cell invasion and motility. In this study, we investigated the role of PKC in breast cancer development and progression. High-density tissue microarray analysis showed that PKC protein was detected in 73.6% (106 of 144) of primary tumors from invasive ductal breast cancer patients. Increasing PKC staining intensity was associated with high histologic grade (P = 0.0206), positive Her2/neu receptor status (P = 0.0419), and negative estrogen (P = 0.0026) and progesterone receptor status (P = 0.0008). Kaplan-Meier analyses showed that PKC was significantly associated with poorer disease-free and overall survival (log-rank, P = 0.0478 and P = 0.0414, respectively). RNA interference of PKC in MDA-MB231 cells, an aggressive breast cancer cell line with elevated PKC levels, resulted in a cell phenotype that was significantly less proliferative, invasive, and motile than the parental or the control RNA interference transfectants. Moreover, in vivo tumor growth of small interfering RNA-PKC MDA-MB231 clones was retarded by a striking 87% (P < 0.05) and incidence of lung metastases was inhibited by 83% (P < 0.02). PKC-deficient clones were found to have lower RhoC GTPase protein levels and activation. Taken together, these results revealed that PKC plays a critical and causative role in promoting an aggressive metastatic breast cancer phenotype and as a target for anticancer therapy.

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