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Molecular diversity of breast cancers at the time of endocrine resistance [mRNA]

ABSTRACT: Dataset containing whole-genome expression profiles of breast cancers at the time of endocrine resistance. It has been used to identify five distinctive phenotypes with different expression of gene clusters associated with ER-signalling, stromal rearrangement and cytokine-signalling. Pathway-focused analysis suggested individual tumours with active ER-signalling (24/55, 44%), PIK3CA-signalling (18/55, 32%), RAS (12/55, 22%) and MYC-signalling (11/55, 20%). 3 or 4 of the above pathways were simultaneously active in 6/55 (11%) cases. Results provide important information about prevalence of different mechanisms of endocrine resistance in clinical samples of breast cancer. Please note that the tumor samples are clinically quite homogeneous: all are post-menopausal ER+ve breast cancers, endocrine treated and growing on treatment. The main purpose of collecting these data was not to compare transcriptional profiles with clinical parameters, but rather to use the transcriptional profiles of these clinically homogeneous tumours for identifying intrinsic subgroups within endocrine resistance. However, the relevant clinical data was also provided as Series supplementary file (ClinicalData_AL28Jan2014.xlsx).

ORGANISM(S): Homo sapiens

PROVIDER: GSE54479 | GEO | 2014/12/01

SECONDARY ACCESSION(S): PRJNA236605

REPOSITORIES: GEO

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Project description:MCM3 is one of several genes whose expression profile is markedly altered in tamoxifen-resistant breast cancer cell lines. We observed that increased MCM3 expression is associated with tamoxifen resistance. Knockdown of MCM3 resulted in increased susceptibility of tamoxifen-resistant breast cancer cell lines. Moreover, MCM3 expression is significantly associated with clinical outcome of endocrine treated receptor positive breast cancer. To understand the effect of MCM3 on the mechanism of endocrine resistance, we performed gene expression array on tamoxifen-resistant breast cancer cell lines. Here we show that MCM3 knockdown affects the expression of hundreds of genes. Resistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancer is a major clinical problem with poorly understood mechanisms. There is an unmet need for prognostic and predictive biomarkers to allow appropriate therapeutic targeting. We evaluated the mechanism by which minichromosome maintenance protein 3 (MCM3) influences endocrine resistance and its predictive/prognostic potential in ER+ breast cancer. We discovered that ER+ breast cancer cells survive tamoxifen and letrozole treatments through upregulation of minichromosome maintenance proteins (MCMs), including MCM3, which are key molecules in cell cycle and DNA replication. Lowering MCM3 expression in endocrine-resistant cells restored drug sensitivity and altered phosphorylation of cell cycle regulators, including p53(Ser315,33), CHK1(Ser317) and cdc25b(Ser323), suggesting that the interaction of MCM3 with cell cycle proteins is an important mechanism of overcoming replicative stress and anti-proliferative effects of endocrine treatments. Evaluation of MCM3 levels in primary tumors from four independent cohorts of breast cancer patients receiving adjuvant tamoxifen mono-therapy or no adjuvant treatment, including the Stockholm tamoxifen (STO-3) trial, showed MCM3 to be an independent prognostic adding information beyond Ki67. In addition, MCM3 was shown to be a predictive marker of response to endocrine treatment. Our study reveals a coordinated signaling network centered around MCM3 that limits response to endocrine therapy in ER+ breast cancer and identifies MCM3 as a clinically useful prognostic and predictive biomarker that allows personalized treatment of ER+ breast cancer patients.

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Molecular diversity of breast cancers at the time of endocrine resistance [mRNA]

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