Abstract B2-10: Systems biology reveals role of cholesterol homeostasis in breast cancer metastasis

Abstract

Abstract New therapeutic targets that can inhibit cancer metastasis are desperately needed. To address this issue, we have leveraged a computational approach and performed an unbiased screen for therapies that can inhibit an epithelial-to-mesenchymal transition (EMT) gene expression profile, a phenotype that is believed to promote metastases. This yielded predictions of drugs that can both promote and inhibit an EMT transcriptional profile. Following up on these predictions, we confirmed experimentally that these drugs can induce or repress an EMT in a range of breast cancer cell lines. Furthermore, we discovered that they do so by altering the fluidity of the plasma membrane. An increase in plasma membrane fluidity is necessary and sufficient to induce and maintain an EMT state, increased motility, and increased mammosphere forming ability. Finally, we found that human cancers can regulate their membrane fluidity through cholesterol homeostasis pathways. Human breast tumors with altered cholesterol profiles have a significantly shorter time to metastasis. These data demonstrate that an unbiased systems approach can be used to discover novel pathways that underlie metastasis. Our multidisciplinary approach combining computational, cell biology, and mouse models reveal that plasma membrane fluidity is a cellular attribute that is leveraged by human tumors to increase metastatic capacity, and that it can, in principle, be targeted by therapeutics to prevent metastasis. Citation Format: Weina Zhao, Prijic Sara, Bettina Urban, Michael Tisza, Sendurai A. Mani, Jeffrey T. Chang. Systems biology reveals role of cholesterol homeostasis in breast cancer metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B2-10.