bc-GenExMiner: an easy-to-use online platform for gene prognostic analyses in breast cancer

Jézéquel, Pascal; Campone, Mario; Gouraud, Wilfried; Guérin‐Charbonnel, Catherine; Leux, Christophe; Ricolleau, G.; Campion, Loı̈c

doi:10.1007/s10549-011-1457-7

Cited by 333 publications

(271 citation statements)

References 22 publications

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“…The phosphorylation of cortactin releases cofilin and leads to the increase of polymerizing actin barbed ends (Oser et al, 2009). By performing prognostic analyses of gene expression in cohorts of breast cancer patients (bc-GenExMiner v3.0; http://bcgenex.centregauducheau.fr; Jézéquel et al, 2012) we found that the overexpression of both CTTN [P,0.0001; hazard ratio (a measure of survival in patients with the condition compared with that of those without), 1.49, 95% confidence interval, 1.26-1.70] and CFL1 (P,0.0001; hazard ratio 1.40, 95% confidence interval, 1.19-1.64) genes were associated with a reduced survival without metastatic relapse (supplementary material Fig. S3A,B) indicating the crucial role of these proteins in cancer cell invasion and the development of metastases.…”

Section: Resultsmentioning

confidence: 99%

NaV1.5 sodium channels allosterically regulate the NHE-1 exchanger and promote breast cancer cell invadopodial activity

Brisson

Driffort

Benoist

et al. 2013

Journal of Cell Science

137

153

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SummaryThe degradation of the extracellular matrix by cancer cells represents an essential step in metastatic progression and this is performed by cancer cell structures called invadopodia. Na V 1.5 (also known as SCN5A) Na + channels are overexpressed in breast cancer tumours and are associated with metastatic occurrence. It has been previously shown that Na V 1.5 activity enhances breast cancer cell invasiveness through perimembrane acidification and subsequent degradation of the extracellular matrix by cysteine cathepsins. Here, we show that Na V 1.5 colocalises with Na + /H + exchanger type 1 (NHE-1) and caveolin-1 at the sites of matrix remodelling in invadopodia of MDA-MB-231 breast cancer cells. NHE-1, Na V 1.5 and caveolin-1 co-immunoprecipitated, which indicates a close association between these proteins. We found that the expression of Na V 1.5 was responsible for the allosteric modulation of NHE-1, rendering it more active at the intracellular pH range of 6.4-7; thus, it potentially extrudes more protons into the extracellular space. Furthermore, Na V 1.5 expression increased Src kinase activity and the phosphorylation (Y421) of the actin-nucleation-promoting factor cortactin, modified F-actin polymerisation and promoted the acquisition of an invasive morphology in these cells. Taken together, our study suggests that Na V 1.5 is a central regulator of invadopodia formation and activity in breast cancer cells.

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Section: Resultsmentioning

confidence: 99%

NaV1.5 sodium channels allosterically regulate the NHE-1 exchanger and promote breast cancer cell invadopodial activity

Brisson

Driffort

Benoist

et al. 2013

Journal of Cell Science

137

153

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“…Medians were compared using the Mann-Whitney U-test for non-normally distributed data, while means were compared using the two-sample t-test for normally distributed data. Kaplan Meier survival curves were produced from online expression databases KMplot (16) and Gene Expression Miner (17). Gene Expression Miner also used publically available expression data to produce a boxplot correlation of FST mRNA level with tumour grade.…”

Section: Methodsmentioning

confidence: 99%

Increased Expression of Follistatin in Breast Cancer Reduces Invasiveness and Clinically Correlates with Better Survival

Zabkiewicz

Resaul

Hargest

et al. 2017

CGP

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Abstract. Background Follistatin (FST) is a secreted extracellular regulatory protein that binds activin and, with less affinity, related TGFβ superfamily members such as bone morphogenetic proteins (BMPs), preventing access to their receptors (1, 2). Originally thought to act on the pituitary to regulate FSH release, FST has subsequently been noted in many other tissues, in particular co-localising with activin resulting in autocrine and paracrine cellular regulation (1, 3). As an antagonist of activin, FST has diverse regulatory roles in embryogenesis, tissue differentiation and repair, gonadal function and inflammatory and immune processes (3, 4).Three major FST isoforms can be produced, namely FST288 (from splice variant mRNA precursor FST317), FST315 (from splice variant mRNA precursor FST344) and a third FST isoform, FST303, produced from the post-translational truncation of the FST315 C-terminus (5). These three main FST isoforms can also be glycosylated to yield six further FST isoforms (6). FST288 and FST315 are differentially expressed in human tissues, but FST315 is the predominant isoform, whilst the FST288 isoform accounts for less than 5% of the encoded mRNA (6, 7) .The FST/activin interaction has been implicated in tumour proliferation, angiogenesis and metastasis in several solid tumours (8-11). Activin has primarily been seen as an inhibitor of cellular proliferation, although certain cell populations seem to be stimulated by activin. Thus, the overall result of activin/FST action in cancer may be both context and cell type specific (3, 6).In the breast, FST is expressed in the normal mammary gland and in different breast proliferative diseases, with additional experimental evidence suggesting that FST can modulate the breast cancer cell cycle (3,(12)(13)(14). However, its role in breast cancer growth and metastasis is far from clear. In this study we demonstrated a clinical correlation between FST expression and survival in breast cancer, and that overexpression of FST in vitro reduces invasion of breast cancer cells. Patients and MethodsCell lines and patient tissue samples. Human breast cell lines MCF-7,MDA MB 231, ZR-751, BT 549 and BT-20 were obtained from and cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% foetal calf serum and antibiotics (PAA Laboratories Ltd., Somerset, UK). Cells were incubated at 37˚C in 5% CO 2 at 95% humidity.Breast cancer tissue and normal breast tissue samples were collected during surgery at the University Hospital of Wales. In total, 93 tumour samples and 30 normal breast tissue samples were obtained from patients who were enrolled in the study. The tissues obtained during surgery were snap-frozen in liquid nitrogen and stored at −80˚C.

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“…Unfortunately, many gene expression arrays previously used in breast cancer outcome studies lacked RIP3 probe sets. However, using the bc-GenExMiner tool designed by Jézéquel et al [36], we analyzed combined data available from 6 studies (1 166 patients). Patients with greater than median RIP3 mRNA expression had a higher probability (P < 0.0085) of metastatic relapse-free survival over a 10-year period ( Figure 5E).…”

Section: Rip3 Expression Is Lost In Primary Breast Cancersmentioning

confidence: 99%

Methylation-dependent loss of RIP3 expression in cancer represses programmed necrosis in response to chemotherapeutics

et al. 2015

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Receptor-interacting protein kinase-3 (RIP3 or RIPK3) is an essential part of the cellular machinery that executes "programmed" or "regulated" necrosis. Here we show that programmed necrosis is activated in response to many chemotherapeutic agents and contributes to chemotherapy-induced cell death. However, we show that RIP3 expression is often silenced in cancer cells due to genomic methylation near its transcriptional start site, thus RIP3-dependent activation of MLKL and downstream programmed necrosis during chemotherapeutic death is largely repressed. Nevertheless, treatment with hypomethylating agents restores RIP3 expression, and thereby promotes sensitivity to chemotherapeutics in a RIP3-dependent manner. RIP3 expression is reduced in tumors compared to normal tissue in 85% of breast cancer patients, suggesting that RIP3 deficiency is positively selected during tumor growth/development. Since hypomethylating agents are reasonably well-tolerated in patients, we propose that RIP3-deficient cancer patients may benefit from receiving hypomethylating agents to induce RIP3 expression prior to treatment with conventional chemotherapeutics.

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bc-GenExMiner: an easy-to-use online platform for gene prognostic analyses in breast cancer

Cited by 333 publications

References 22 publications

NaV1.5 sodium channels allosterically regulate the NHE-1 exchanger and promote breast cancer cell invadopodial activity

NaV1.5 sodium channels allosterically regulate the NHE-1 exchanger and promote breast cancer cell invadopodial activity

Increased Expression of Follistatin in Breast Cancer Reduces Invasiveness and Clinically Correlates with Better Survival

Methylation-dependent loss of RIP3 expression in cancer represses programmed necrosis in response to chemotherapeutics

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