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AIB1 dependent transcriptome in endocrine resistance

ABSTRACT: Purpose: AIB1 expression is associated with disease progression in aromastase inhibitor (AI) treated patients in breast cancer. In order to identify genes aberrantly regulated by AIB1 in AI resistance, RNA-seq was carried out in endocrine resistant LetR cells and endocrine sensitive MCF7 cells +/- AIB1 under estrogen deprivation. Methods: RNA-seq was carried out in biological triplicate in MCF7 and LetR cells comparing NT (Scramble siRNA) cells versus cells depleted of AIB1 using a SMARTpool ON-TARGETplus siRNA. RNA was extracted using Qiagen RNeasy Kit and subjected to 100bp PE sequencing using the BGISEQ 500 platform. Briefly, clean reads were mapped to reference genome using Bowtie2 and gene expression was calculated with RSEM. Differentially expressed genes (DEGs) were detected with DEseq2. With the KEGG pathway analysis, the pathway functional enrichment was performed using phyper, a function of R. Results: 61 AIB1 differentially regulated genes were identified as unique to endocrine resistant tumor cells (logfc≥1.5; Padj≤0.05).MSigDB Oncogenic signature analysis of the 61 AIB1-regulated genes revealed enrichment in growth promoting endocrine resistance pathways including LTE2, RAF, ERBB2 and MEK. Conclusion: In the endocrine resistant setting, aberrant AIB1 expression regulates the expression of genes associated with growth factor signalling.

ORGANISM(S): Homo sapiens

PROVIDER: GSE158095 | GEO | 2020/12/30

REPOSITORIES: GEO

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Project description:Resistance to endocrine therapy agents has presented a clinical obstacle in the treatment of hormone-dependent breast cancer. Our laboratory has initiated a study of microRNA regulation of signaling pathways that may result in breast cancer progression on aromatase inhibitors (AI). Microarray analysis of microRNA expression identified 115 significantly regulated microRNAs, of which 49 microRNAs were believed to be hormone-responsive. Within the AI-resistant cells, microRNAs were differentially expressed between the steroidal and non-steroidal AI-resistant lines. Also, a group of microRNAs were inversely expressed in the AI-resistant lines versus LTEDaro and tamoxifen-resistant. We focused our work on hsa-miR-128a which was hormone-responsive and up-regulated in the letrozole-resistant cell lines. Human miR-128a was shown to negatively target TGFBRI protein expression by binding to the 3âUTR region of the gene. Loss of TGFBRI resulted in compromised sensitivity to the growth inhibitory effects of TGFB in the letrozole-resistant lines. Inhibition of endogenous miR-128a resulted in re-sensitization of the letrozole-resistant lines to TGFB growth inhibitory effects. This data suggests that the hormone-responsive miR-128a can modulate TGFB signaling and survival of the letrozole-resistant cell lines. To our knowledge, this is the first study to address the role of microRNA regulation as well as TGFB signaling in AI-resistant breast cancer cell lines. We believe that in addition to estrogen-modulation of gene expression, hormone-regulated microRNAs may provide an additional level of post-transcriptional regulation of signaling pathways critically involved in breast cancer progression and AI-resistance. To look at microRNA expression profiles of breast cancer cell lines derived from MCF-7 cells that are resistant to endocrine therapy agents. MCF-7 cells that overexpress aromatase (MCF-7aro) were cultured long-term in the presence of endocrine therapy agents until cells acquired resistance. Three different aromatase inhibitors (letrozole, anastrozole or exemestane) were used, as well as the ER antagonist tamoxifen, or the hormone-free long-term estrogen deprived cells (LTED). Three replicates of the control cells (MCF-7aro) and all resistant cells were used for microarray experiments. Total of 23 samples were analyzed by microarray.

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AIB1 dependent transcriptome in endocrine resistance

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