A candidate molecular signature associated with tamoxifen failure in primary breast cancer

Vendrell, Julie A.; Robertson, Katherine; Ravel, Patrice; Bray, Susan E.; Bajard, Agathe; Purdie, Colin A.; Nguyen, Catherine; Hadad, Sirwan; Bièche, Ivan; Chabaud, Sylvie; Bachelot, Thomas; Thompson, Alastair; Cohen, Pascale A.

doi:10.1186/bcr2158

Cited by 56 publications

(45 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Three complementary analytical techniques were used to analyze transcriptome profiling data with subsequent immunohistochemical confirmation of selected genes [23]. This revealed several consistent and biologically plausible observations despite asymmetry in the timing of the metformin (day 0 v day 14) and control (day 0 v day 7 or day 0 v day 14) biopsies, and unequal sample sizes of the various cohorts.…”

Section: Discussionmentioning

confidence: 76%

Evidence for biological effects of metformin in operable breast cancer: a pre-operative, window-of-opportunity, randomized trial

Hadad

Inomata

Jordan

et al. 2011

Breast Cancer Res Treat

264

199

View full text Add to dashboard Cite

, Colin Purdie, Susan Bray, et al.. Evidence for biological effects of metformin in operable breast cancer: a pre-operative, window-of-opportunity, randomized trial. Breast Cancer Research and Treatment, Springer Verlag, 2011, 128 (3) AbstractMetformin may reduce the incidence of breast cancer and enhance response to neoadjuvant chemotherapy in diabetic women. This trial examined the effects of metformin on Ki67 and gene expression in primary breast cancer.Non-diabetic women with operable invasive breast cancer received pre-operative metformin. A pilot cohort of 8 patients had core biopsy of the cancer at presentation, a week later (without treatment; internal control), then following metformin 500mg o.d. for one week increased to 1g b.d. for a further week continued to surgery. A further 47 patients had core biopsy at diagnosis, were randomized to metformin (the same dose regimen) or no drug, and 2 weeks later had core biopsy at surgery. Ki67 immunohistochemistry, transcriptome analysis on formalin fixed paraffin embedded cores and serum insulin determination were performed blinded to treatment.7 patients (7/32, 21.9%) receiving metformin withdrew due to gastrointestinal upset. The mean percentage of cells staining for Ki67 fell significantly following metformin treatment in both the pilot cohort (p=0.041, paired t-test) and in the metformin arm (p=0.027, Wilcoxon rank test) but was unchanged in the internal control or metformin control arms. Messenger RNA expression was significantly down-regulated by metformin for PDE3B (phosphodiesterase 3B, cGMP-inhibited; a critical regulator of cAMP levels which affect activation of AMP-activated protein kinase, AMPK), confirmed by immunohistochemistry, SSR3, TP53 and CCDC14. By Ingenuity Pathway Analysis, the Tumour Necrosis Factor Receptor 1 (TNFR1) signaling pathway was most affected by metformin: TGFB, MEKK were up-regulated and cdc42 down-regulated; mTOR and AMPK pathways were also affected. Gene Set Analysis additionally revealed that p53, BRCA1 and cell cycle pathways also had reduced expressed following metformin. Mean serum insulin remained stable in patients receiving metformin but rose in control patients.This trial presents biomarker evidence for anti-proliferative effects of metformin in women with breast cancer and provides support for therapeutic trials of metformin.

show abstract

Section: Discussionmentioning

confidence: 76%

Evidence for biological effects of metformin in operable breast cancer: a pre-operative, window-of-opportunity, randomized trial

Hadad

Inomata

Jordan

et al. 2011

Breast Cancer Res Treat

264

199

View full text Add to dashboard Cite

show abstract

“…Total RNA was extracted from frozen tumor samples as previously described (19). Gene expression data from Ma and colleagues' study (ref.…”

Section: Breast Tumor Cohortsmentioning

confidence: 99%

ZNF217 Is a Marker of Poor Prognosis in Breast Cancer That Drives Epithelial–Mesenchymal Transition and Invasion

et al. 2012

View full text Add to dashboard Cite

The Kr€ uppel-like zinc finger protein ZNF217 is a candidate oncogene in breast cancer. In this study, we showed that high levels of expression of ZNF217 mRNA are associated with poor prognosis and the development of metastases in breast cancer. Overexpression of ZNF217 in breast cancer cells stimulated migration and invasion in vitro and promoted the development of spontaneous lung or node metastases in mice in vivo. ZNF217 also promoted epithelial-mesenchymal transition (EMT) in human mammary epithelial cells, and the TGF-b-activated Smad signaling pathway was identified as a major driver of ZNF217-induced EMT. In addition, a TGF-b autocrine loop sustained activation of the TGF-b pathway in ZNF217-overexpressing mammary epithelial cells, most likely because of ZNF217-mediated direct upregulation of TGFB2 or TGFB3. Inhibition of the TGF-b pathway led to the reversal of ZNF217-mediated EMT. Together, our findings indicate that ZNF217 mRNA expression may represent a novel prognostic biomarker in breast cancer. Therapeutic targeting of ZNF217 of the TGF-b signaling pathway may benefit the subset of patients whose tumors express high levels of ZNF217. Cancer Res; 72(14); 3593-606. Ó2012 AACR.

show abstract

“…Although this may seem incongruent, in breast tissue, BCL-2 is regulated by estrogen and is associated with high ER expression, although its expression is not simply a surrogate for ER expression (13)(14)(15). Low BCL-2 expression is included in several molecular signatures associated with acquired resistance to endocrine therapy and poor prognosis in primary breast cancer (16)(17)(18). Because diminished BCL-2 expression in cancer confers increased sensitivity to cytotoxic chemotherapy, it is possible that breast cancer patients with endocrine-resistant disease could achieve significant therapeutic benefit from cytotoxic agents when used as a second-line treatment.…”

Section: Introductionmentioning

confidence: 99%

BCL-2 Hypermethylation Is a Potential Biomarker of Sensitivity to Antimitotic Chemotherapy in Endocrine-Resistant Breast Cancer

Stone

Cowley

Valdés-Mora

et al. 2013

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Overexpression of the antiapoptotic factor BCL-2 is a frequent feature of malignant disease and is commonly associated with poor prognosis and resistance to conventional chemotherapy. In breast cancer, however, high BCL-2 expression is associated with favorable prognosis, estrogen receptor (ER) positivity, and low tumor grade, whereas low expression is included in several molecular signatures associated with resistance to endocrine therapy. In the present study, we correlate BCL-2 expression and DNA methylation profiles in human breast cancer and in multiple cell models of acquired endocrine resistance to determine whether BCL-2 hypermethylation could provide a useful biomarker of response to cytotoxic therapy. In human disease, diminished expression of BCL-2 was associated with hypermethylation of the second exon, in a region that overlapped a CpG island and an ER-binding site. Hypermethylation of this region, which occurred in 10% of primary tumors, provided a stronger predictor of patient survival (P ¼ 0.019) when compared with gene expression (n ¼ 522). In multiple cell models of acquired endocrine resistance, BCL-2 expression was significantly reduced in parallel with increased DNA methylation of the exon 2 region. The reduction of BCL-2 expression in endocrine-resistant cells lowered their apoptotic threshold to antimitotic agents: nocodazole, paclitaxel, and the PLK1 inhibitor BI2536. This phenomenon could be reversed with ectopic expression of BCL-2, and rescued with the BCL-2 inhibitor ABT-737. Collectively, these data imply that BCL-2 hypermethylation provides a robust biomarker of response to current and next-generation cytotoxic agents in endocrine-resistant breast cancer, which may prove beneficial in directing therapeutic strategy for patients with nonresectable, metastatic disease. Mol Cancer Ther; 12(9); 1874-85. Ó2013 AACR.

show abstract

A candidate molecular signature associated with tamoxifen failure in primary breast cancer

Cited by 56 publications

References 68 publications

Evidence for biological effects of metformin in operable breast cancer: a pre-operative, window-of-opportunity, randomized trial

Evidence for biological effects of metformin in operable breast cancer: a pre-operative, window-of-opportunity, randomized trial

ZNF217 Is a Marker of Poor Prognosis in Breast Cancer That Drives Epithelial–Mesenchymal Transition and Invasion

BCL-2 Hypermethylation Is a Potential Biomarker of Sensitivity to Antimitotic Chemotherapy in Endocrine-Resistant Breast Cancer

Contact Info

Product

Resources

About