Abstract A027: Endothelial-like properties of triple-negative claudin-low breast cancer cells promote tumor-vascular interactions and tumor permeability

Abstract

Abstract The different intrinsic subtypes of human breast tumors vary in rate and location of metastatic dissemination. In this study, we aimed to determine if tumor-associated vascular properties could help to explain the differences observed in metastagenicity. We used endothelial and breast cancer cell line models to develop gene expression signatures that measured vascular quantity and vascular proliferation. We tested these signatures, amongst other published endothelial signatures, and found that the genomic programs that measured vascular quantity, vascular proliferation, and a VEGF/Hypoxia-signature were the most highly expressed in claudin-low and basal-like tumors. We then tested the vascular signatures on five human breast cancer datasets (n>3,000) and identified two vascular signatures that added prognostic information to intrinsic subtype classification. Next, microvessel density (MVD) scores were obtained from a set of 70 tumors which were also subjected to gene expression profiling. Interestingly, several of the vascular signatures added metastasis-predicting information in addition to MVD (p<0.05). Similar to the tumor data, claudin-low cell lines also expressed high levels of vascular gene signatures as compared to luminal cell lines. Interestingly, pure claudin-low cell lines, and subsets of claudin-low-like cells within established basal-like cell cancer cell lines, exhibited endothelial-like morphology when culture on Matrigel. In vivo xenografts of claudin-low tumors, but not luminal tumors, extensively perfused injected contrast agent through paracellular spaces and non-vascular tumor-lined channels. Taken together, the endothelial-like characteristics of the cancer cells, combined with both the amount and the physiologic state of the vasculature, contribute to breast cancer metastatic progression. We hypothesize that the genetic signatures we have identified highlight patients that should respond most favorably to anti-vascular agents. Citation Format: J. Chuck Harrell, Adam Pfefferle, Nicole Zalles, Aleix Prat, Cheng Fan, Andrey Khramtsov, Olufunmilayo Olopade, Melissa Troester, Andrew Dudley, Charles Perou. Endothelial-like properties of triple-negative claudin-low breast cancer cells promote tumor-vascular interactions and tumor permeability. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A027.