Abstract A40: Protein disulfide isomerases in the endoplasmic reticulum promote anchorage-independent growth of breast cancer cells

Cancer cells that separate from primary tumors and migrate to metastatic sites are exposed to stress caused by detachment from the extracellular matrix (ECM). Cultured breast cancer cells that survive this stress and are capable of anchorage-independent proliferation form mammospheres. Biological mechanisms responsible for maintaining the mammosphere-growth competence are not fully understood. We hypothesized that mammosphere growth requires elevated ECM secretion, which demands efficient folding quality control in the endoplasmic reticulum (ER). We found that SUM159PT and MCF10DCIS.com breast cancer cells grown as mammospheres had elevated mRNA and protein levels of three protein disulfide isomerases: ERp57, ERp44, and PDI. We also found an increased phosphorylation of eIF2alpha in mammospheres, suggesting that the PERK arm of the unfolded protein response was activated. An inducible knock-down of ERp57 in SUM159PT cells resulted in impaired ability to form mammospheres. Analysis of a publicly available gene expression data for circulating tumor cells (CTCs) revealed that up-regulation of ECM genes and ER folding quality control genes occurred at the time of disease progression and surge in the number of CTCs. These data indicate that breast cancer cell survival and growth under detachment conditions require enhanced assistance of the ER folding machinery in the correct disulfide bond formation. Citation Format: Randi Wise, Sara Duhachek-Muggy, Yue Qi, Michal Zolkiewski, Anna Zolkiewska. Protein disulfide isomerases in the endoplasmic reticulum promote anchorage-independent growth of breast cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A40.