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Cholesterol biosynthesis pathway as a novel mechanism of resistance to estrogen deprivation in estrogen receptor positive breast cancer

ABSTRACT: Therapies targeting estrogenic stimulation in estrogen receptor positive (ER+) breast cancer (BC) reduce mortality, but resistance remains a major clinical problem. Molecular studies have shown few high frequency mutations to be associated with endocrine resistance. In contrast, expression profiling of primary ER+ BC samples has identified several promising signatures/networks for targeting. In this study, the cholesterol biosynthesis pathway was the common upregulated pathway in the ER+ LTED but not ER- LTED cell lines, suggesting a potential mechanism dependent on continued ER expression. Targeting the individual genes of the cholesterol biosynthesis pathway with siRNAs caused a 30-50% drop in proliferation. Further analysis showed increased expression of 25-hydroxycholesterol (HC) in the MCF7 LTED cells. Exogenous 25-HC or 27-HC increased ER mediated-transcription and expression of the endogenous estrogen-regulated gene TFF1 in ER+ LTED cells but not in the ER-negative LTED. Additionally, recruitment of the ER and CREB-binding protein (CBP) to the TFF1 promoter was increased upon treatment with 25-HC and 27-HC. In silico analysis of 704 primary ER+ BC patients treated with adjuvant tamoxifen showed increased expression of MSMO1 (p=0.047), EBP (p=0.043), SQLE (p=0.000009), and IDI1 (p=0.0005), enzymes required for cholesterol synthesis and increased in our in vitro models of endocrine resistance, to be associated with poor relapse-free survival. In contrast, no association was identified in over 700 patients with ER-negative BC. Taken together, these data provide support for the role of cholesterol biosynthesis enzymes and the cholesterol metabolites, 25-HC and 27-HC, in a novel mechanism of resistance to endocrine therapy in ER+ BC that has potential as a therapeutic target.

ORGANISM(S): Homo sapiens

PROVIDER: GSE75971 | GEO | 2016/05/20

SECONDARY ACCESSION(S): PRJNA305878

REPOSITORIES: GEO

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Project description:Phosphoinositide-3-kinase/protein-kinaseB/mammalian target of rapamycin (PI3K/AKT/mTOR) signalling plays an important role in breast cancer (BC). Its interaction with estrogen receptor (ER) signalling becomes more complex and inter-dependent with acquired endocrine resistance. Targeting mTOR combined with endocrine therapy has shown clinical utility, however, a negative feedback-loop exists downstream of PI3K/AKT/mTOR. Direct blockade of AKT together with endocrine therapy may improve BC treatment. AZD5363, a novel pan-AKT kinase catalytic inhibitor, was examined in a panel of ER+ BC cell lines (MCF7, HCC1428, T47D, ZR75.1) adapted to long-term-estrogen-deprivation (LTED) or tamoxifen (TamR). AZD5363 caused a dose-dependent decrease in proliferation in all cell lines tested (GI50<500nM) except HCC1428 and HCC1428-LTED. T47D-LTED and ZR75-LTED were the most sensitive of the lines (GI50~100nM). AZD5363 re-sensitised TamR cells to tamoxifen and acted synergistically with fulvestrant. AZD5363 decreased p-AKT/mTOR targets leading to a reduction in ERα-mediated transcription in a context specific manner and concomitant decrease in recruitment of ER and CREB-binding protein (CBP) to estrogen-response-elements located on the TFF1, PGR and GREB1 promoters. Furthermore, AZD5363 reduced expression of cell-cycle-regulatory proteins. Global gene expression highlighted ERBB2-ERBB3, ERK5 and IGF1 signaling pathways driven by MYC as potential feedback-loops. Combined treatment with AZD5363 and fulvestrant showed synergy in an ER+ patient derived xenograft and delayed tumour progression post-cessation of therapy. These data support the combination of AZD5363 with fulvestrant as a potential therapy for BC that is sensitive or resistant to E-deprivation or tamoxifen and that activated AKT is a determinant of response, supporting the need for clinical evaluation. Cell lines were treated in biological triplicates in the absence of estrogen with or without AZD5363 for 24hours in order to identify gene changes associated with perturbation of AKT signalling

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Cholesterol biosynthesis pathway as a novel mechanism of resistance to estrogen deprivation in estrogen receptor positive breast cancer

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