Abstract P4-05-10: PRKCQ, a novel protein kinase C preferentially expressed in triple negative breast cancer, drives oncogenic growth, survival and migration

Abstract

Abstract Background/Rationale: PRKCQ, a member of the novel protein kinase C family, was identified in a functional genomic screen for regulators of anoikis resistance/anchorage-independent survival (Irie et al., 2010). Interestingly, it is preferentially expressed in the triple negative/basal subtype of breast tumors compared to Luminal or Her2+ tumors. We sought to determine the functional role of PRKCQ in triple negative breast cancer and evaluate PRKCQ as a candidate therapeutic target for this subtype. Materials and Methods. Consistent with its expression in triple negative patient breast tumors, PRKCQ is also highly expressed in several triple negative breast cancer cell lines. We utilized both gain- and loss-of-function approaches in these cell lines to determine the requirement for PRKCQ in oncogenic growth and survival using in vitro and in vivo models. Results. Isoform-specific downregulation of PRKCQ using shRNA vectors severely impaired growth of triple negative breast cancer cells in 2D monolayer and 3D Matrigel cultures. In 3D cultures, PRKCQ downregulation not only inhibited growth, but impaired the formation of invasive branching. PRKCQ downregulation also inhibited the growth of MDA231 primary tumor xenografts. All of these data support a requirement for PRKCQ expression in triple negative breast cancer cell growth. To determine if PRKCQ is sufficient to drive oncogenic phenotypes, we overexpressed PRKCQ in a non-transformed immortalized breast epithelial cell line, MCF-10A. PRKCQ expression conferred EGF-independent growth, migration and anoikis resistance. In PRKCQ-expressing MCF-10A cells, EGFR phosphorylation and activation were preserved in the absence of exogenous EGF ligand addition. We are currently elucidating the mechanisms responsible for PRKCQ-mediated, sustained activation of EGFR. Conclusions. PRKCQ is critically required for growth of triple negative breast cancer cells. Increased expression of PRKCQ is sufficient to drive oncogenic, growth factor-independent growth, survival and migration. Interestingly, PRKCQ could play a dual role in the development of triple negative breast cancer, as it may also function in the immune microenvironment to support the growth of these tumors. Therefore, PRKCQ is an attractive candidate therapeutic target for patients with triple negative breast cancer. Citation Format: Hanna Y Irie, Gwyneth Halstead-Nussloch, Koichi Ito. PRKCQ, a novel protein kinase C preferentially expressed in triple negative breast cancer, drives oncogenic growth, survival and migration [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-05-10.