Adjuvant Statin Therapy Efficacy is Dictated by Tumor Dormancy and Statin Lipophilicity in Ex Vivo and In Vivo Models of Metastatic Breast Cancer

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 metastatic emergent (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, a hallmark of emergent outgrowth. 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. Statins were further found in vivo to influence breast cancer metastasis and metastatic growth using a mouse model of spontaneous liver metastases. 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. Support or Funding Information NCATS/NCI (UH3TR000496) to AW and NCI F30 (1F30CA199947), CATER Training Program (T32 EB001026), and Pitt/CMU MSTP Program (5T32GM008208) to CB