Transdifferentiation between Luminal- and Basal-Type Cancer Cells.

摘要

Breast cancer is a highly diverse group of cancers and consists of at least 5 different subgroups. Furthermore, patients with Intra-tumor heterogeneity due to the presence of cancer cells with variable phenotypes such as different degrees of basal-like and luminal features increase the complexity of treatment. The aim of this project is to better understand the mechanisms that regulate breast cancer cell plasticity and origins of breast cancer heterogeneity. Our focus is the function of protein kinase D1 (PKD1), which is a serine/threonine kinase. We previously showed that PKD1 can repress epithelial to mesenchymal transition (EMT) by inhibitory phosphorylation of transcription factor Snail, a master switch of EMT. Supported by this award, we have performed experiments on molecular, cellular, mice xenografts and transgenic levels and conclude that PKD1 is a context-dependent tumorigenesis and metastasis repressor or enhance. Specifically, PKD1 is a metastasis repressor in luminal type breast cancer and loss of PKD1 in luminal type cells converts them into basal-like cells; and PKD1 is an enhancer of tumorigenesis in basal-like breast cancer. Based on current available data, conditional knockout PKD1 in mouse mammary tissue does not disrupt mammary development and does not induce tumorigenesis. However, when combination with P53 mutant, loss of PKD1 greatly enhances tumor incidence and metastasis rate, suggesting an anti-cancer role of PKD1 this study is still in progression, final results will be available after one more year.