Gene signature associated with resistance to fluvastatin chemoprevention for breast cancer

Abstract

Background Although targeting of the cholesterol pathway by statins prevents breast cancer development in mouse models, efficacy is not absolute. Therefore, the goal of this study is to investigate if the upregulation in the cholesterol biosynthesis pathway genes associates with response to statin chemoprevention and may potentially be used as response biomarkers. Methods Expression of cholesterol biosynthesis pathway genes was initially derived from the RNA sequencing of MCF10A cell line- based breast cancer progression model system and subsequently validated by quantitative PCR assay. Response to fluvastatin was assessed in vitro using the MCF10A cell line model system, including a statin resistant cell line that was generated (MCF10.AT1-R), and measured using colony forming assays. In vivo efficacy of statin for chemoprevention was assessed in the SV40C3 TAg mouse model. Mammary tumors were identified by histologic analysis of the mammary glands. Mammary glands without histologic evidence of high-grade lesions (in situ and/or invasive carcinoma) were considered responsive to statin treatment. Results We found more than 70% of a published multi-gene fluvastatin resistance signature to be significantly upregulated during breast cancer progression and inversely correlated with statin inhibition of cellular growth and proliferation. This inherent statin resistance gene signature was also largely shared with the signature of acquired resistance to fluvastatin in MCF10.AT1-R cell line model of acquired statin resistance. These inherent resistance genes and genes exclusive to acquired statin resistance map to steroid-, and terpenoid backbone- biosynthesis pathway. We found upregulation of ~ 80% of cholesterol biosynthesis pathway genes in the tumor bearing mammary glands of SV40 C3TAg transgenic mouse model of TNBC, suggesting the involvement of cholesterol biosynthesis pathway in resistance to statin chemoprevention in vivo. A panel of 13-genes from the pathway significantly associated with response to statin treatment, as did the expression level of HMGCR alone in a mouse model of breast cancer suggesting their utility to predict the efficacy of statin chemoprevention. Conclusions High basal level, or restorative upregulation, in the cholesterol biosynthesis pathway genes appear to be strongly associated with resistance to statin chemoprevention for breast cancer and may serve as a biomarker to tailor statin treatment to individuals who are most likely to benefit.

Therapeutic trial of fluvastatin in a cell line xenograft model of canine mammary gland cancer

“…In this regard, future mechanistic studies could evaluate HMGCR expression in vivo in tumours treated or not with statin, as well as in metastases to assess any potential effect of the tumour microenvironment. Other groups also reported cancer cell line resistance to statins in prostate and breast cancers 44,47,48 possibly through a feedback response that leads to an upregulation of HMG‐CoA reductase through the activation of sterol regulatory element‐binding protein 2 (SREBP2). In future studies, it would be interesting to evaluate the ability of CMT‐9 cell line to activate SREBP2 and trigger the expression of sterol metabolism in response to fluvastatin treatment.…”

The Link Between Statins and Breast Cancer in Mouse Models: A Systematic Review

“…However, when combined with another anti-cancer agent, statins appeared to have a greater effect compared to statins alone, suggesting a synergistic benefit with established anti-cancer agents. The studies classified as chemoprevention found significantly delayed tumor onset, albeit using only one statin [29][30][31].…”

“…The three studies investigating statin chemoprevention in this review exclusively modeled the progression of triple-negative breast cancer (TNBC), an aggressive form of breast cancer histologically known for absent to low concentrations of estrogen (ER), progesterone (PR), and human epidermal growth factor 2 (HER2) protein receptors. As the molecular breast cancer phenotype with the most aggressive histology and poorest outcomes, it tends to be more commonly studied in the context of statins in an effort to reveal the efficacy and mechanisms of novel and repurposed therapies [29][30][31].…”

“…They ultimately concluded that the upregulation of certain cholesterol biosynthesis genes such as HMGCR could contribute to driving the invasive disease. The authors highlighted the importance of screening and identifying women with associated gene upregulations and suggest avoiding statin therapy for these subsets due to their resistant phenotype [ 30 ]. The authors also recommended targeting statin therapy to at-risk populations more likely to respond.…”

MiR-122-5p regulates the mevalonate pathway by targeting p53 in non-small cell lung cancer

“…Although the genes of the MVA pathway are not strictly highly expressed in NSCLC, our study showed that the high expression of MVA pathway genes was associated with more severe cancer lesions; thus, targeting the MVA pathway might be a promising therapeutic strategy in cancer treatment 6 . At present, anti-tumor drugs targeting the MVA pathway can be roughly divided into three categories according to their targets: anti-HMGCR, anti-FDPS and anti-SREBP2 3,24,40,48 . The former two are represented by statins and bisphosphonates and achieved good therapeutic results 9,47 while targeting SREBP2 to treat cancer has broader research prospects.…”