Abstract
BackgroundEndocrine resistance in estrogen receptor-positive (ER+) breast cancer is a major clinical problem and is associated with accelerated cancer cell growth, increased motility and acquisition of mesenchymal characteristics. However, the specific molecules and pathways involved in these altered features remain to be detailed, and may be promising therapeutic targets to overcome endocrine resistance.MethodsIn the present study, we evaluated altered expression of epithelial-mesenchymal transition (EMT) regulators in ER+ breast cancer cell models of tamoxifen or fulvestrant resistance, by gene expression profiling. We investigated the specific role of increased SNAI2 expression in fulvestrant-resistant cells by gene knockdown and treatment with a SNAIL-p53 binding inhibitor, and evaluated the effect on cell growth, migration and expression of EMT markers. Furthermore, we evaluated SNAI2 expression by immunohistochemical analysis in metastatic samples from two cohorts of patients with breast cancer treated with endocrine therapy in the advanced setting.ResultsSNAI2 was found to be significantly upregulated in all endocrine-resistant cells compared to parental cell lines, while no changes were observed in the expression of other EMT-associated transcription factors. SNAI2 knockdown with specific small interfering RNA (siRNA) converted the mesenchymal-like fulvestrant-resistant cells into an epithelial-like phenotype and reduced cell motility. Furthermore, inhibition of SNAI2 with specific siRNA or a SNAIL-p53 binding inhibitor reduced growth of cells resistant to fulvestrant treatment. Clinical evaluation of SNAI2 expression in two independent cohorts of patients with ER+ metastatic breast cancer treated with endocrine therapy in the advanced setting (N = 86 and N = 67) showed that high SNAI2 expression in the metastasis correlated significantly with shorter progression-free survival on endocrine treatment (p = 0.0003 and p = 0.004).ConclusionsOur results suggest that SNAI2 is a key regulator of the aggressive phenotype observed in endocrine-resistant breast cancer cells, an independent prognostic biomarker in ER+ advanced breast cancer treated with endocrine therapy, and may be a promising therapeutic target in combination with endocrine therapies in ER+ metastatic breast cancer exhibiting high SNAI2 levels.
Highlights
Endocrine resistance in estrogen receptor-positive (ER+) breast cancer is a major clinical problem and is associated with accelerated cancer cell growth, increased motility and acquisition of mesenchymal characteristics
Our results suggest that SNAI2 is a key regulator of the aggressive phenotype observed in endocrine-resistant breast cancer cells, an independent prognostic biomarker in ER+ advanced breast cancer treated with endocrine therapy, and may be a promising therapeutic target in combination with endocrine therapies in ER+ metastatic breast cancer exhibiting high SNAI2 levels
The epithelial-mesenchymal transition (EMT) transcription regulator SNAI2 is upregulated in endocrine-resistant breast cancer cells To identify EMT-associated genes involved in the endocrine-resistant phenotype of breast cancer cells, we evaluated whether several EMT regulators exhibited altered expression in our gene expression profiling data from MCF-7-based fulvestrant-resistant and tamoxifen-resistant cell lines [18, 23]
Summary
Endocrine resistance in estrogen receptor-positive (ER+) breast cancer is a major clinical problem and is associated with accelerated cancer cell growth, increased motility and acquisition of mesenchymal characteristics. There is considerable evidence suggesting that acquisition of endocrine resistance is accompanied by accelerated tumor growth and increased metastatic propensity, and is associated with morphological changes characteristic of cells undergoing epithelial-mesenchymal transition (EMT) [2]. Key questions remain regarding the central molecules controlling the EMT process during development of endocrine resistance, which may be promising therapeutic targets in combination with endocrine therapy. EMT has been associated with increased cell migration capacity and invasiveness, and is a prominent hallmark of cancer progression [4, 5]. EMT and MET are regulated by signals from the stroma associated with tumors, such as transforming growth factor (TGF)-β, and by a series of EMT-inducing transcription factors, including SNAI1, SNAI2, TWIST, ZEB1 and ZEB2 [7]
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