Statins attenuate outgrowth of breast cancer metastases

Colin H Beckwitt,Diana Whaley,Bo Ma,Amanda M Clark,Zoltán N Oltvai,Alan Wells

doi:10.1038/s41416-018-0267-7

Abstract

BackgroundMetastasis in breast cancer foreshadows mortality, as clinically evident disease is aggressive and generally chemoresistant. Disseminated breast cancer cells often enter a period of dormancy for years to decades before they emerge as detectable cancers. Harboring of these dormant cells is not individually predictable, and available information suggests that these micrometastatic foci cannot be effectively targeted by existing therapies. As such, long-term, relatively non-toxic interventions that prevent metastatic outgrowth would be an advance in treatment. Epidemiological studies have found that statins reduce breast cancer specific mortality but not the incidence of primary cancer. However, the means by which statins reduce mortality without affecting primary tumor development remains unclear.MethodsWe examine statin efficacy against two breast cancer cell lines in models of breast cancer metastasis: a 2D in vitro co-culture model of breast cancer cell interaction with the liver, a 3D ex vivo microphysiological system model of breast cancer metastasis, and two independent mouse models of spontaneous breast cancer metastasis to the lung and liver, respectively.ResultsWe demonstrate that statins can directly affect the proliferation of breast cancer cells, specifically at the metastatic site. In a 2D co-culture model of breast cancer cell interaction with the liver, we demonstrate that atorvastatin can directly suppress proliferation of mesenchymal but not epithelial breast cancer cells. Further, in an ex vivo 3D liver microphysiological system of breast cancer metastasis, we found that atorvastatin can block stimulated emergence of dormant breast cancer cells. In two independent models of spontaneous breast cancer metastasis to the liver and to the lung, we find that statins significantly reduce proliferation of the metastatic but not primary tumor cells.ConclusionsAs statins can block metastatic tumor outgrowth, they should be considered for use as long-term adjuvant drugs to delay clinical emergence and decrease mortality in breast cancer patients.

Highlights

Breast cancer is responsible for the second highest number of female cancer deaths and alone accounts for 30% of all new cancer diagnoses in women.[1]
Mesenchymal breast cancer cells that lack membrane E-cadherin are more sensitive to atorvastatin suppression We previously demonstrated that membrane E-cadherin was a marker and mechanism of resistance to atorvastatin treatment, whereas vimentin did not correlate with atorvastatin resistance.[27]
Atorvastatin suppresses proliferation of breast cancer liver metastases but not the primary tumor Since we found atorvastatin was able to suppress the stimulated outgrowth of breast cancer cells in the liver microphysiological system (MPS), we wanted to examine whether systemic atorvastatin administration in a mouse model for spontaneous breast cancer metastasis to the liver would show the same affect

Summary

Introduction

Breast cancer is responsible for the second highest number of female cancer deaths and alone accounts for 30% of all new cancer diagnoses in women.[1]. Disseminated breast cancer cells often enter a period of dormancy for years to decades before they emerge as detectable cancers. Harboring of these dormant cells is not individually predictable, and available information suggests that these micrometastatic foci cannot be effectively targeted by existing therapies. In two independent models of spontaneous breast cancer metastasis to the liver and to the lung, we find that statins significantly reduce proliferation of the metastatic but not primary tumor cells. CONCLUSIONS: As statins can block metastatic tumor outgrowth, they should be considered for use as long-term adjuvant drugs to delay clinical emergence and decrease mortality in breast cancer patients

Methods

Results

Conclusion