Table 1. Overview of included studies.

EtOH: ethanol; TNBC: triple-negative breast cancer; qPCR: quantitative polymerase chain reaction; HMGCR: 3-hydroxy-3-methylglutaryl-CoA reductase; BRCA1: breast cancer gene 1; BrdU: bromodeoxyuridine; CDK4: cyclin-dependent kinase 4; pRb: retinoblastoma protein; DMBA: 12-dimethylbenz(a)anthracene; DMSO: dimethyl sulfoxide; PTEN: phosphatase and tensin homolog; AKT: protein kinase B; RhoB: ras homolog family member B; Bcl: B-cell lymphoma 2; MCM7: minichromosome maintenance complex component 7; HDACi: histone deacetylase inhibitor; HER2: human epidermal growth factor receptor 2; Erbb2: Erb-B2 receptor tyrosine kinase 2; MNU: methylnitrosourea; ER: estrogen receptor; DKK-1: dickkopf-1; PSV: polyethylene glycol-s-s-vitamin E succinate; Ki-67: antigen KI-67; Gy: gray 

Author (Year)	Study Design	Animal Model(s)	Outcomes Measured	Findings/Conclusions
Statins as Chemoprevention
Bhardwaj (2021) [27]	Fluvastatin (10 mg/kg/day) vs. Vehicle control (0.001% EtOH) for 16 wks	5-6 wk old SV40C3 TAg transgenic TNBC mouse model	Tumor incidence, multiplicity, weight, latency	Significant delay in onset of tumors (20 wks vs. 16.8 wks) and 75% reduction in tumor weight compared to control.
Bhardwaj (2022) [28]	Fluvastatin (10 mg/kg/day) vs. Vehicle control (0.001% EtOH) for 16 wks	5-6 wk old SV40C3 TAg transgenic TNBC mouse model	Tumor histologic grade and qPCR evaluation of fluvastatin-resistant gene signatures	Upregulation of cholesterol biosynthesis pathway genes in mice mammary tumors is strongly associated with resistance to statin chemoprevention.
Bhardwaj (2018) [29]	Fluvastatin (10 mg/kg/day) vs. Control (water) for 16 wks	5 wk old MCF10.AT1 xenograft TNBC mouse model	Tumor size, histologic grade, HMGCR mRNA level	25% reduction in tumor size of fluvastatin-treated mice compared to control. No difference in histologic grade of tumors between groups.
Statins as Chemotherapy
Monotherapy
Karimi (2019) [30]	Simvastatin (40 or 80 mg/kg/day) vs. tamoxifen (50 mg/kg/day) vs. Control (sesame oil)	5 wk old DMBA-treated mouse model (50 mg/kg/day)	Tumor size, weight, volume, oxidative stress biomarkers of serum, mammary glands, and tumors	Tamoxifen and high dose simvastatin improved carcinogenic parameters and lessened the severity of oxidative stress, a driver of breast cancer progression, compared to control.
Ghosh Choudhury (2010) [31]	Simvastatin (5 mg/kg/day) vs. control (phosphate-buffer saline) for 1 wk	2 wk old MDA-MB-231 mammary tumoral xenograft mouse model	Quantification of phosphorylated AKT, Bcl, PTEN	Simvastatin significantly increases levels of tumor suppressor PTEN while simultaneously downregulating anti-apoptotic molecule Bcl.
Ma (2019) [32]	Atorvastatin (10 mg/kg/day) vs. DMSO control	4 wk old MCF-7 intramammary tumoral xenograft mouse model	Tumor size, volume, weight, mRNA/protein expression of RhoB, PTEN, AKT	Atorvastatin has carcinostatic effects that act via the PTEN/AKT pathway.
Li (2017) [33]	Simvastatin (60 mg/kg/day) vs. control (water) for 10 days	4T1 breast carcinoma xenograft mouse model	Tumor size, weight, volume, MCM7 and RB protein expression, %MCM7+ and RB+ cells	Decreased expression of RB and MCM7 create genome instability and thus induce apoptosis in simvastatin-treated mammary carcinoma mice xenografts.
Yu (2008) [34]	Lovastatin (10 mg/kg/day) vs. Placebo (0.9% NaCl) for 2 wks	8 wk old MCF-7/BRCA1 tumoral xenograft mouse model	Anti-proliferation via BrdU and mRNA/protein expression of cyclin D1, CDK4, pRb, and p21	BRCA1 overexpression revealed significantly enhanced anti-proliferation and reduced cell cycle mRNA and protein levels in lovastatin-treated breast tumoral xenograft mice models.
Combination Therapy
Wnt Signaling Pathway
Sulaiman (2018) [35]	Simvastatin + Wnt inhibitor ICG-001 & atorvastatin + zoledronic acid, respectively	MDA-MB-231 xenograft TNBC mouse model	Tumor weight, relative cancer stem cell concentrations, survival, serum DKK-1 levels	Statin and Wnt inhibitor combination therapy shows reduction in tumor weight and cancer stem cell populations for both epithelial and mesenchymal phenotypes. No concrete conclusions can be drawn from decreased DKK-1 levels.
Göbel (2015) [36]
HER2+ breast cancer
Oechsle (2020) [37]	Simvastatin + dendritic cell-based immunotherapy & lovastatin + lapatinib, respectively	HCC1954 & TUBO xenograft HER2+ mouse models, respectively	Tumor size, volume, weight, relative Erbb2 protein%	Two different combination therapy regimens showed synergistic benefit of overall tumor reduction in HER2+ breast cancer animal models. Molecular concentrations of Erbb2 protein are reduced as well.
Zhang (2019) [38]
HR+ breast cancer
Liang (2017) [39]	Simvastatin + tamoxifen & atorvastatin + tamoxifen, respectively	Tamoxifen-resistant MCF7 xenograft mouse model & MNU-induced ER+ rat model, respectively	Tumor size, weight, volume, incidence, multiplicity, MCM7 protein expression	In optimal doses, statin plus tamoxifen is synergistic against hormone receptor positive tumors. However, in suboptimal doses, limited synergistic potential exists.
Lubet (2009) [40]
HDACi therapy
Kou (2017) [41]	Simvastatin + vorinostat & mevastatin + pabinostat, respectively	MDA-MB-231 xenograft TNBC mouse model for all studies	Tumor size, volume, weight, survival, apoptosis biomarkers	Combination HDACi therapy with statins induced significant growth suppression and apoptosis compared to monotherapy or control. Future preclinical and clinical studies should seek to investigate the effect of chemotherapy and other statins.
Kou (2018) [42]
Lin (2017) [43]
Statins as Anti-metastatic agents
Beckwitt (2018) [23]	Atorvastatin (2 mg/kg/day) vs. atorvastatin (10 mg/kg/day) vs. vehicle control for 3 wks	8 wk old NSG MDA-MB-231 liver & lung metastatic mouse model	Tumor size and proliferation, metastatic burden and proliferation in lung and liver models	Atorvastatin shows dose-dependent decreases in metastatic proliferation, but not primary tumor cell proliferation in both lung and liver metastasis models.
Xu (2014) [44]	Atorvastatin-loaded PSV micelle (5 mg/kg/day) vs. free atorvastatin (5 mg/kg/day) vs. control (saline) for 18 days	4T1 orthotopic mammary tumor metastatic cancer mouse model	Animal weight, tumor volume, number of metastatic nodules	Atorvastatin-loaded PSV micelles significantly reduced the number of pulmonary metastatic nodules by 84.8% compared to free atorvastatin.
Wolfe (2015) [45]	Simvastatin (15 mg/kg/day) vs. control (DMSO) for 7 wks	4 wk old SUM 149 & MDA-MB-231 orthotopic & tail vein injection metastasis mouse model	Number of lung and brain metastases, metastasis free survival	Significantly lower number of brain metastases and longer metastasis free survival is seen in simvastatin treated mice.
Howe (2020) [46]	Pitavastatin (1 mg/kg/day) vs. simvastatin (5 mg/kg/day) vs. vehicle control	MDA-231 intracardiac & intracranial breast cancer brain metastasis mouse model	Brain mets incidence, Ki-67 staining quantification, survival	Decreased brain metastasis incidence, decreased metastatic proliferation, and increased survival are apparent in statin treated metastasis mouse models.
Mandal (2011) [47]	Simvastatin (5 mg/kg/day) vs. control (phosphate-buffer saline) for 1 wk	MDA-MB-231 mammary tumor bone metastasis mouse model	Osteolytic lesion visualization and quantification	Compared to control mice, simvastatin-treated mice demonstrated significantly reduced bone lesions and thus prevents breast cancer bone metastasis.
Wang (2019) [48]	Pitavastatin (4 or 8 mg/kg/day) vs. vehicle control for 3 wks	6 wk old 4T1.2 tibial bone metastasis mouse model	Tibial visualization, bone volume, bone mineral density, number of osteolytic lesions	In an osteolytic model of breast cancer, high dose pitavastatin played a protective role in bone metastasis compared to placebo.
Vintonenko (2012) [49]	Fluvastatin (15 mg/kg/day) vs. zoledronate (100 µg/kg) vs. control (phosphate-buffered saline) for 3 wks	Intracardiac bioluminescent MDA-MB-231 TNBC mouse model	Bioluminescent signal of treated mice, number of detected metastatic sites, survival of treated mice	Fluvastatin treatment reduced the overall metastatic burden compared to control and contributed increased survival compared to the other 2 groups.
Marti (2021) [50]	Atorvastatin (10 mg/kg/day) + doxorubicin (2 mg/kg)/paclitaxel (10 mg/kg)	MDA-MB-231 spleen to liver xenograft	Metastatic proliferation quantification	Doxorubicin, but not paclitaxel, combined with statins show potential useful benefit in a primary spleen to metastatic liver mouse model.
Efimova (2018) [51]	Pitavastatin (20 mg/kg/day) + 6Gy tumor irradiation	MCF7 xenograft mouse model	Tissue damage & cellular senescence	Alone, pitavastatin has minimal effects on breast tumor-bearing mice, however, in combination with ionizing radiation, DNA damage and decreased proliferation are enhanced.