A novel and feasible strategy to specifically inhibit PKCα expression and tumor development

• Main Authors: Chia-herng Yue, 于家珩
• Other Authors: 林赫
• Format: Others
• Language: en_US
• Published: 2015
• Online Access: http://ndltd.ncl.edu.tw/handle/24007809072343933484

博士 === 國立中興大學 === 生命科學系所 === 103 === Breast cancer is the leading cause of women malignancy in the world with an increasing trend in recent decades whether in Western country or Asia. The modern westernized life style with high fat food accompany with the high prevalence. Several types of breast cancer had been classified upon pathological feature according to expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (Her-2). However, the triple negative breast cancer had no expression of above receptors which made it more difficult in treatment since there was no space for hormone and target therapy in treating patient. Therefore the triple negative breast cancer had easy recurrence and metastasis with poor outcome. Recent reports demonstrated that the expression of protein kinase C alpha (PKCα) in triple-negative breast cancer (TNBC) is correlated with poorer survival outcomes. However, the mechanism of the enhanced expression of PKCα in TNBC remains greatly unknown. In the present study, our results showed that the presence of both myeloid zinc finger 1 (MZF-1) and Ets-like protein-1 (Elk-1) expressions correlate to PKCα expression in TNBC. Furthermore, it is the interaction between the acidic domain of MZF-1 and the heparin-binding domain of Elk-1 which facilitated their heterodimeric complex formation before their binding to the PKCα promoter. Blocking the formation of the heterodimer changed Elk-1 nuclear localization, MZF-1 protein degradation, their DNA-binding activities, and subsequently the expression of PKCα in TNBC cells. Thus, migration, tumorigenicity, and epithelial–mesenchymal transition potential of TNBC cells decreased, suggesting that the Elk-1/MZF-1 heterodimer is considered as a mediator of PKCα in TNBC cell malignancy. The obtained data also suggested that the next therapeutic strategy in the treatment of TNBC will come from the blocking of Elk-1/MZF-1 interaction through the saturation of Elk-1 or MZF-1 binding domains, such as through the application of cell-penetrating HIV transactivating regulatory protein-fused peptides to inhibit tumor growth and metastasis.