Abstract
The protein kinase C (PKC) family has been functionally linked to cancer. It has been suggested that atypical PKCs contribute to cell proliferation and cancer progression. With respect to breast cancer, PKCζ has been found to play a key role in intracellular transduction of mitogenic and apoptotic signals using mammary cell lines. However, little is known about its function in vivo. Here we examined the correlation between PKCζ protein levels and important clinicopathologic factors in breast cancer using patient samples. To conduct the study, 30 invasive ductal carcinoma cases and their paired normal tissues were used for tissue microarray analysis (TMA) and 16 were used for western blot analysis. In addition, the correlation between PKCζ expression levels and clinicopathologic characteristics was determined in 176 cases with relevant clinical data. Finally, the correlation between PKCζ and epithelial growth factor receptor 2 (HER2) expressions was determined using three breast cancer cell lines by western blot analysis. Both TMA and western blot results showed that PKCζ protein was highly expressed in primary tumors but not in paired normal tissue. The correlation study indicated that high PKCζ levels were associated with premenopausal patients (p = 0.019) and worse prognostic factors, such as advanced clinical stage, more lymph node involvement and larger tumor size. Both disease-free survival and overall survival rates were lower in the high PKCζ group than those in the low PKCζ group. No correlation was observed between PKCζ levels and age, histological grade, or estrogen or progesterone receptor expression status. A positive correlation between PKCζ and HER2 levels was observed in both tumor samples and cell lines. Our observations link PKCζ expression with factors pointing to worse prognosis, higher HER2 levels and a lower survival rate. This suggests that PKCζ protein levels may serve as a prognostic marker of breast cancer.
Highlights
Protein kinase C (PKC) displays key regulatory roles in a wide variety of fundamental cellular processes, including signal transduction, regulation of gene expression and cell cycle control
Thirty paired samples were analyzed using tissue microarray analysis (TMA), and the number of invasive samples that scored positive for PKCf (17/30, 56.7%) was much higher than that for normal samples (3/30, 10%) (p,0.01)
Greater than 50% of breast cancer specimens overexpressed PKCf, and PKCf that were related to pathological and prognostic characteristics, including clinical stage, lymph node metastasis status, tumor size, human epithelial growth factor receptor 2 (HER2) status and survival rate
Summary
Protein kinase C (PKC) displays key regulatory roles in a wide variety of fundamental cellular processes, including signal transduction, regulation of gene expression and cell cycle control. The unique N-terminal regulatory domain on aPKCs interacts with partitioning-defective (PAR)-3 and PAR-6 proteins, which play roles in asymmetrical cell division and cell polarization processes [7]. During cancer progression, this interaction is involved in the epithelial-to-mesenchymal transition that is characteristic of the invasive phenotype associated with metastatic carcinomas [8,9,10]
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