| First Author | Allen-Petersen BL | Year | 2014 |
| Journal | Oncogene | Volume | 33 |
| Issue | 10 | Pages | 1306-15 |
| PubMed ID | 23474764 | Mgi Jnum | J:212377 |
| Mgi Id | MGI:5578716 | Doi | 10.1038/onc.2013.59 |
| Citation | Allen-Petersen BL, et al. (2014) Protein kinase Cdelta is required for ErbB2-driven mammary gland tumorigenesis and negatively correlates with prognosis in human breast cancer. Oncogene 33(10):1306-15 |
| abstractText | Protein kinase C delta (PKCdelta) regulates apoptosis in the mammary gland, however, the functional contribution of PKCdelta to the development or progression of breast cancer has yet to be determined. Meta-analysis of ErbB2-positive breast cancers shows increased PKCdelta expression, and a negative correlation between PKCdelta expression and prognosis. Here, we present in-vivo evidence that PKCdelta is essential for the development of mammary gland tumors in a ErbB2-overexpressing transgenic mouse model, and in-vitro evidence that PKCdelta is required for proliferative signaling downstream of the ErbB2 receptor. Mouse mammary tumor virus (MMTV)-ErbB2 mice lacking PKCdelta (deltaKO) have increased tumor latency compared with MMTV-ErbB2 wild-type (deltaWT) mice, and the tumors show a dramatic decrease in Ki-67 staining. To explore the relationship between PKCdelta and ErbB2-driven proliferation more directly, we used MCF-10A cells engineered to express a synthetic ligand-inducible form of the ErbB2 receptor. Depletion of PKCdelta with short hairpin RNA inhibited ligand-induced growth in both two-dimensional (2D) (plastic) and three-dimensional (3D) (Matrigel) culture, and correlated with decreased phosphorylation of the ErbB2 receptor and reduced activation of Src and MAPK/ERK pathways. Similarly, in human breast cancer cell lines in which ErbB2 is overexpressed, depletion of PKCdelta suppresses proliferation, Src and ERK activation. PKCdelta appears to drive proliferation through the formation of an active ErbB2/PKCdelta/Src signaling complex, as depletion of PKCdelta disrupts association of Src with the ErbB2 receptor. Taken together, our studies present the first evidence that PKCdelta is a critical regulator of ErbB2-mediated tumorigenesis, and suggest further investigation of PKCdelta as a target in ErbB2-positive breast cancer. |
