Dataset Information

Gene Expression of A375 Cells After Fluvastatin Treatment

ABSTRACT: Despite advances in melanoma treatment, more than 70% of patients with distant metastasis die within 5 years. Proactive treatment of early melanoma to prevent metastasis could save lives and reduce overall healthcare costs. Currently, there are no treatments specifically designed to prevent early melanoma from progressing to metastasis. We used the Connectivity Map (cMap) to conduct an in silico drug screen and identified HMGCR inhibitors (statins) as a drug class that might prevent melanoma metastasis. To confirm the in vitro effect of statins, RNA-sequencing was completed on A375 cells after treatment with fluvastatin to describe changes in the melanoma transcriptome. Statins induced differential expression in genes associated with metastasis and used in commercially available prognostic tests for melanoma metastasis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE160870 | GEO | 2023/11/04

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Background: Cholesterol pathway inhibition by statins prevents breast cancer development in mouse models of breast cancer but their efficacy is not very high (about 50%) . Therefore, the goal of this study is to investigate if the fluvastatin mediated upregulation in the steroid biosynthesis pathway genes limit the efficacy of statin chemoprevention. Methods: A published gene signature of statin resistance was validated in cell line-based models of inherent and acquired resistance during breast cancer. These signatures were next validated in a mouse model of hormone receptor negative breast cancer. Results: We found more than 70% of a published multi-gene fluvastatin resistance signature to be significantly upregulated in an inherently resistant cell line relative to fluvastatin sensitive cell line. We found this inherent statin resistance gene signature to be also shared with the signature of acquired resistance to fluvastatin (13 / 23 total genes). These 13 inherent resistance genes and 10 additional genes mapped to 2 of the top 3 deregulated pathways that are steroid-, and terpenoid backbone- biosynthesis pathway. Next, we tested if one or multiple genes of statin resistance signature, could predict efficacy of statin chemoprevention in the SV40 C3TAg transgenic mouse model. We found upregulation of a large number (19/24) of genes in the tumor bearing mammary glands, suggesting that upregulation of these pathways drives resistance to statin chemoprevention. A subset of 13-genes from this panel was significantly associated with response to statin treatment, as was the expression level of HMGCR alone in a mouse model of breast cancer. Lastly, we studied if a 10-day period of fluvastatin treatment to SV40C3 TAg mice, can also trigger the upregulation of these genes and provide an early signal of statin resistance. These experiments showed that a 10-day period is insufficient to cause a feedback upregulation in steroid biosynthesis pathway genes and thus cannot be used as an early biomarker to detect resistance to fluvastatin. Conclusions: High basal or restorative upregulation in the steroid biosynthesis pathway gene expression after fluvastatin treatment appears to be strongly associated with resistance to statin chemoprevention for breast cancer and may serve as a biomarker to identify patients that are most likely to respond to statins or develop resistance.

Project description:Statins and bisphosponates (BPs) are two distinct classes of isoprenoid pathway inhibitors targeting HMG-CoA reductase (upstream enzyme) and Farnesyl-pyrophospate synthase (downstream enzyme) respectively. Here we conducted a comparative study of two representatives of these classes, fluvastatin (Fluva) and Zoledronate (Zol), to assess the differences in their in vivo metastatic potentials and pharmacogenomic profiles. Both drugs, being administered after emergence of detectable metastases, appeared to be potent metastasis inhibitors in MDA-MB-231 breast cancer metastasis model. We observed a reduced number of metastatic sites under Fluva, but not Zol treatment. Combinatorial in vivo treatment by Fluva and Zol showed no synergy for these drugs, as reported earlier on the basis of in vitro studies (Budman DR, Oncology 2006), staying in line with similarity of their transcriptomic profiles. Comparison of Zol and Fluva transcriptomic profiles revealed similar patterns of affected genes (describe involved genes functions) through different kinetics (when treated with IC50 determined for 72h treatment, the majority of changes were observed after 24h incubation with Fluva , and only after 48h incubation with Zol at 72h-IC50 or after 24h treatment with its 3 times higher dose). We demonstrated here that targeting different enzymes of the same pathway neither necessarily leads to distinct changes in gene profiles, nor to synergy for in vivo anti-metastatic potential. Subconfluent MDA-MB-321 cells were treated with 2 ÂµM Fluvastatine or 30 ÂµM Zoledronate (concentrations corresponding to IC50 at 72h treatment) for 12h and 24h , or treated with Zoledronate for longer time (48h at 30 ÂµM) or with higher concentration (24h at 100 ÂµM of Zoledronate ). Mock-treated (control) cells were obtained in parallel for each time point. Four independent replicates were used for each condition. Total of 40 samples were analyzed (10 conditions with 4 replicates for each). To determine differentially expressed genes, differences between treated cells versus corresponding mock-treated control were calculated using R-Bioconductor statistical environment. Pairing was made to remove source of variation due to the day of measurement in the comparison between the two conditions.

Dataset Information

Gene Expression of A375 Cells After Fluvastatin Treatment

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets