Association of tamoxifen resistance and lipid reprogramming in breast cancer

Abstract

BackgroundTamoxifen treatment of estrogen receptor (ER)-positive breast cancer reduces mortality by 31%. However, over half of advanced ER-positive breast cancers are intrinsically resistant to tamoxifen and about 40% will acquire the resistance during the treatment.MethodsIn order to explore mechanisms underlying endocrine therapy resistance in breast cancer and to identify new therapeutic opportunities, we created tamoxifen-resistant breast cancer cell lines that represent the luminal A or the luminal B. Gene expression patterns revealed by RNA-sequencing in seven tamoxifen-resistant variants were compared with their isogenic parental cells. We further examined those transcriptomic alterations in a publicly available patient cohort.ResultsWe show that tamoxifen resistance cannot simply be explained by altered expression of individual genes, common mechanism across all resistant variants, or the appearance of new fusion genes. Instead, the resistant cell lines shared altered gene expression patterns associated with cell cycle, protein modification and metabolism, especially with the cholesterol pathway. In the tamoxifen-resistant T-47D cell variants we observed a striking increase of neutral lipids in lipid droplets as well as an accumulation of free cholesterol in the lysosomes. Tamoxifen-resistant cells were also less prone to lysosomal membrane permeabilization (LMP) and not vulnerable to compounds targeting the lipid metabolism. However, the cells were sensitive to disulfiram, LCS-1, and dasatinib.ConclusionAltogether, our findings highlight a major role of LMP prevention in tamoxifen resistance, and suggest novel drug vulnerabilities associated with this phenotype.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4757-z) contains supplementary material, which is available to authorized users.

The significance of lipid accumulation in breast carcinoma cells through perilipin 2 and its clinicopathological significance

“…Those lipid droplets were considered to induce cell proliferation of ER‐negative, not ER‐positive, breast carcinoma cell lines . However, in ER‐positive T47D cells, lipid droplets were also reported to be involved in development of therapeutic resistance to the anti‐proliferative effects of docetaxel and tamoxifen . Therefore, the roles of lipid droplets in breast carcinoma cells may be different depending on intrinsic subtypes but further investigations such as prognostic analysis in each subtype are required to clarify the clinical or biological significance of perilipin 2 in breast carcinomas.…”

Metabolic Plasticity in Chemotherapy Resistance

“…It has been demonstrated that tamoxifen-resistant breast cells, T-47D, present an increased level of neutral lipids, in particular, cholesterol esters and triglycerides, and increased expression of Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) (121). CDDP-resistant human ovarian cancer cell lines shift their metabolism toward a lipogenic phenotype and accumulate lipid droplets (244).…”

Moonlighting Proteins and Cardiopathy in the Spatial Response of MCF‐7 Breast Cancer Cells to Tamoxifen

“…The protective role of 4‐OHT against cardiovascular diseases appears to be indirectly due to lipid reprogramming mediated by drug and to the cholesterol pathway association to altered gene expression patterns that can partially explain the Tam resistance of cells . Thus the downregulation of most proteins showed in Figure A could indicate a positive impact of Tam on cardiomyopathy pathways in MCF‐7 cell.…”