Abstract P1-01-20: Adjuvant statin therapy efficacy is dictated by tumor dormancy and statin lipophilicity in ex vivo and in vivo models of metastatic breast cancer

Abstract

Abstract Metastasis in breast cancer patients heralds mortality, as disseminated disease is generally chemoresistant. After tumor cells reach the ectopic tissue, they undergo an epithelial reversion to enter a period of quiescence, termed dormancy, which may last for decades before outgrowing again as mesenchymal/dedifferentiated masses. Thus, long-term, relatively non-toxic interventions that prevent metastatic outgrowth are needed to treat this mortal stage of tumor progression. Epidemiological analyses have suggested that statin usage, for cardiovascular indications, is correlated with a reduction in clinically-evident metastatic (though not in incidence of primary) breast cancer. The goal of this study is to demonstrate this is due to statins suppressing breast cancer cell proliferation and keeping the micrometastases in the dormant state. We have found that atorvastatin and simvastatin limit the growth of some cancer cell lines, but not others. The sensitive lines were marked by lacking surface E-cadherin, the hallmark of the mesenchymal phenotype. When E-cadherin is downregulated on epithelial tumor cells, the cells become growth inhibited by the statins. Furthermore, this is a direct effect, as we now have shown that hydrophilic statins are relatively ineffective compared to the membrane permeant lipophilic statins as tumor cells generally lack the transporters that enable these drugs to gain access to the cells. To determine whether the statins target the emergent metastatic tumor cells, we are using an all human microphysiological system (MPS) of the most common site for metastases, the liver. Briefly, a micro-hepatic tissue is established by seeding primary human liver cells in a porous scaffold subject to a physiological flow. RFP-labeled breast cancer cells are seeded into these microtissues and examined weeks later. Liver function and health are monitored by clinical chemistry assays performed on supernatant samples. We have previously shown that this system robustly reproduces tumor dormancy. Initial studies suggest that statins suppress the emergence of dormant tumor cells when challenged by stressors that lead to outgrowth. Additionally, atorvastatin suppresses proliferation of mesenchymal but not epithelial breast cancer cells in intrasplenic and mammary fat pad injection models for breast cancer metastasis to the liver and lung respectively. As 26% of adults currently take a statin for other medical conditions, these studies may suggest the best statin to use in the context of maintaining breast cancer dormancy long-term and delaying or avoiding the morbid emergence. Citation Format: Beckwitt CH, Clark AM, Warita K, Oltvai ZN, Wells A. Adjuvant statin therapy efficacy is dictated by tumor dormancy and statin lipophilicity in ex vivo and in vivo models of metastatic breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-01-20.