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The estrogen and c-Myc target gene HSPC111 is over-expressed in breast cancer and associated with poor patient outcome.

ABSTRACT: INTRODUCTION: Estrogens play a pivotal role in the initiation and progression of breast cancer. The genes that mediate these processes are not fully defined, but potentially include the known mammary oncogene MYC. Characterization of estrogen-target genes may help to elucidate further the mechanisms of estrogen-induced mitogenesis and endocrine resistance. METHODS: We used a transcript profiling approach to identify targets of estrogen and c-Myc in breast cancer cells. One previously uncharacterized gene, namely HBV pre-S2 trans-regulated protein 3 (HSPC111), was acutely upregulated after estrogen treatment or inducible expression of c-Myc, and was selected for further functional analysis using over-expression and knock-down strategies. HSPC111 expression was also analyzed in relation to MYC expression and outcome in primary breast carcinomas and published gene expression datasets. RESULTS: Pretreatment of cells with c-Myc small interfering RNA abrogated estrogen induction of HSPC111, identifying HSPC111 as a potential c-Myc target gene. This was confirmed by the demonstration of two functional E-box motifs upstream of the transcription start site. HSPC111 mRNA and protein were over-expressed in breast cancer cell lines and primary breast carcinomas, and this was positively correlated with MYC mRNA levels. HSPC111 is present in a large, RNA-dependent nucleolar complex, suggesting a possible role in ribosomal biosynthesis. Neither over-expression or small interfering RNA knock-down of HSPC111 affected cell proliferation rates or sensitivity to estrogen/antiestrogen treatment. However, high expression of HSPC111 mRNA was associated with adverse patient outcome in published gene expression datasets. CONCLUSION: These data identify HSPC111 as an estrogen and c-Myc target gene that is over-expressed in breast cancer and is associated with an adverse patient outcome.

SUBMITTER: Butt AJ

PROVIDER: S-EPMC2397527 | biostudies-literature | 2008

REPOSITORIES: biostudies-literature

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The estrogen and c-Myc target gene HSPC111 is over-expressed in breast cancer and associated with poor patient outcome.

Butt Alison J AJ Sergio C Marcelo CM Inman Claire K CK Anderson Luke R LR McNeil Catriona M CM Russell Amanda J AJ Nousch Marco M Preiss Thomas T Biankin Andrew V AV Sutherland Robert L RL Musgrove Elizabeth A EA

Breast cancer research : BCR 20080329 2

<h4>Introduction</h4>Estrogens play a pivotal role in the initiation and progression of breast cancer. The genes that mediate these processes are not fully defined, but potentially include the known mammary oncogene MYC. Characterization of estrogen-target genes may help to elucidate further the mechanisms of estrogen-induced mitogenesis and endocrine resistance.<h4>Methods</h4>We used a transcript profiling approach to identify targets of estrogen and c-Myc in breast cancer cells. One previousl ...[more]

PMID: 18373870

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Project description:Breast carcinoma (BC) is the leading cause of death in women worldwide, making up 23% of all cancers in women, with 1.38 million new cases worldwide annually and responsible for 460,000 deaths. Despite the significant advances in the identification of molecular markers and different modalities of treatment in primary BC, the ability to predict the metastatic behavior in breast cancer is still limited. The purpose of this study was to help identify novel molecular markers associated with clinical outcome in a cohort of Brazilian BC patients. We generated global gene expression profiles from 24 patients with invasive ductal BC followed for â¥ 5-years, including 15 samples from patients classified as presenting good prognosis based on traditional markers and clinical criteria and 9 patients that developed metastasis. We identified a set of 58 differentially expressed genes (p â¤0.01) between groups of patients with good and poor prognosis. Up-regulation of B3GNT7, PPM1D, TNKS2, PHB and GTSE1 in patients with poor prognosis was confirmed by quantitative RT-PCR in an independent sample set from patients with BC (47 with good prognosis and 8 that presented metastasis). Expression of BAD protein was investigated by immunohistochemistry in 1276 BC samples and confirmed the reduced expression levels in metastatic cases observed in the oligoarray data. These findings point to novel prognostic markers that can distinguish breast carcinoma samples according to clinical course and progression of the disease. Global expression profiles from 38 ductal breast tumor patient samples were used to search for molecular signatures correlated with current prognostic markers. A subset of 24 cases comprising 15 patients that remained free of disease after surgery and 9 patients that developed metastasis was used to identify candidate biomarkers associated with metastatic progression. Candidates were subsequently validated in additional independent samples by RT-qPCR or immunohistochemistry.

Dataset Information

The estrogen and c-Myc target gene HSPC111 is over-expressed in breast cancer and associated with poor patient outcome.

Publications

The estrogen and c-Myc target gene HSPC111 is over-expressed in breast cancer and associated with poor patient outcome.

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