Statins attenuate outgrowth of breast cancer metastases

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.

Attempts to use statins in cancer therapy: An update

“…In vivo, in two independent models of breast cancer metastasis to liver and to lung, atorvastatin reduced proliferation of the metastatic, but not the primary, tumour cells. 66 Interestingly, in a large panel of cancer cell lines of multiple cancer types, it was shown that enrichment of EMT features in cells is associated with increased sensitivity to statins, which is independent from prenylation of RAS family proteins. 67…”

Simvastatin Suppresses Human Breast Cancer Cell Invasion by Decreasing the Expression of Pituitary Tumor-Transforming Gene 1

“…Recently, both preclinical and clinical studies have demonstrated beneficial effects of statins on breast cancer management ( Van Wyhe et al, 2017 ; Beckwitt et al, 2018a ; Li et al, 2019 ). Indeed, several in vitro and animal experiments have shown that statins exert positive anti-tumor effects by increasing breast cancer apoptosis ( Åberg et al, 2008 ; Kamel et al, 2017 ), preventing carcinogenesis ( Denoyelle et al, 2001 ), and inhibiting tumor growth ( Wolfe et al, 2015 ; Beckwitt et al, 2018b ). It should be noted that while most clinical studies showed positive effects of statins in management of breast cancer patients, while some clinical studies showed no or even opposite results ( Borgquist et al, 2018 ).…”

“…Recently, statins have also received attention regarding unpredictable benefits to reduce breast cancer progression and mortality ( Liu et al, 2015 ; Borgquist et al, 2018 ; Gobel et al, 2019 ) and restrain breast cancer cell migration ( Ginestier et al, 2012 ; Van Wyhe et al, 2017 ; Gobel et al, 2019 ). Particularly, simvastatin, as one of the most commonly used statins, has demonstrated significant beneficial effects in reducing breast cancer metastasis and recurrence ( Ahern et al, 2011 ; Chae et al, 2011 ; Clendening and Penn, 2012 ; Beckwitt et al, 2018b ; Li et al, 2019 ). However, the underlying mechanisms by which statins inhibit tumor cell metastasis are not fully understood, although several studies have implicated the Rho/ROCK pathway, which is inhibited by statin treatment, as a key mechanism involved in regulation of cancer survival, proliferation, and invasion by statins ( Denoyelle et al, 2001 ; Demierre et al, 2005 ).…”

Statin drugs to reduce breast cancer recurrence and mortality

“…Moreover, simvastatin treatment reduced the activity of Rho associated protein kinase (ROCK) and expression of RhoC, chemokine receptor type 4 (CXCR4), and CD44 [ 94 ]. In a sophisticated ex vivo microphysiological model of breast cancer metastasis to the liver, breast cancer outgrowth in response to an inflammatory lipopolysaccharide/EGF stimulus could be suppressed with atorvastatin treatment [ 95 ]. Finally, we have shown in mouse models of spontaneous breast cancer metastasis to liver and lung that atorvastatin is able to suppress metastatic proliferation but not the proliferation of the primary tumor [ 95 ].…”

“…In a sophisticated ex vivo microphysiological model of breast cancer metastasis to the liver, breast cancer outgrowth in response to an inflammatory lipopolysaccharide/EGF stimulus could be suppressed with atorvastatin treatment [ 95 ]. Finally, we have shown in mouse models of spontaneous breast cancer metastasis to liver and lung that atorvastatin is able to suppress metastatic proliferation but not the proliferation of the primary tumor [ 95 ]. These data suggest that statins preferentially target mesenchymal, metastatic cells.…”