NT5E CpG island methylation is a favourable breast cancer biomarker

Nigro, Cristiana Lo; Monteverde, Martino; Lee, S; Lattanzio, Laura; Vivenza, Daniela; Comino, A.; Syed, Nelofer; McHugh, Angela; Wang, H; Proby, Charlotte M.; Garrone, Ornella; Merlano, Marco; Hatzimichael, Eleftheria; Briasoulis, Evangelos; Gojiš, Ondřej; Palmieri, Carlo; Jordan, Lee B.; Quinlan, P; Thompson, Alastair; Crook, Tim

doi:10.1038/bjc.2012.212

Cited by 36 publications

(52 citation statements)

References 30 publications

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“…Although CD73 expression has been documented in various types of cancer, including breast cancer, correlative analysis to clinical outcome has been limited (30). Herein we show that CD73 expression in breast cancer is higher in the TNBC subtype and that TNBC patients with high CD73 expression have a higher risk of distant metastases, the main cause of death from breast cancer.…”

Section: Discussionmentioning

confidence: 69%

CD73 promotes anthracycline resistance and poor prognosis in triple negative breast cancer

Loi

Pommey

Haibe‐Kains

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

416

392

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Using gene-expression data from over 6,000 breast cancer patients, we report herein that high CD73 expression is associated with a poor prognosis in triple-negative breast cancers (TNBC). Because anthracycline-based chemotherapy regimens are standard treatment for TNBC, we investigated the relationship between CD73 and anthracycline efficacy. In TNBC patients treated with anthracycline-only preoperative chemotherapy, high CD73 gene expression was significantly associated with a lower rate of pathological complete response or the disappearance of invasive tumor at surgery. Using mouse models of breast cancer, we demonstrated that CD73 overexpression in tumor cells conferred chemoresistance to doxorubicin, a commonly used anthracycline, by suppressing adaptive antitumor immune responses via activation of A2A adenosine receptors. Targeted blockade of CD73 enhanced doxorubicin-mediated antitumor immune responses and significantly prolonged the survival of mice with established metastatic breast cancer. Taken together, our data suggest that CD73 constitutes a therapeutic target in TNBC.ectonucleotidase | immunogenic cell death | immunotherapy T riple-negative breast cancer (TNBC), as defined by the absence of estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2) expression, accounts for 15-20% of all breast cancers (1). Compared with other breast cancer subtypes, TNBC is characterized by a worse prognosis and increased risk of metastasis to vital organs (1). There are currently no known molecular targets for this subgroup of breast cancer patients and there seem to be few therapeutic options on the horizon, especially given that the development of poly (ADP ribose) polymerase and EGFR inhibitors have been thus far disappointing (2). Hence, the treatment of TNBC is a significant challenge in today's clinical practice and the identification of therapeutic targets an area of urgent clinical need (3).Cytotoxic chemotherapy, particularly anthracycline-based regimens, therefore remains the mainstay of treatment for TNBC today. Although TNBC is associated with a poor prognosis, some patients seem to respond well to anthracycline-based chemotherapy, reflecting a significant degree of molecular heterogeneity within this subgroup (3-5). Unfortunately, the molecular mechanisms underlying this heterogeneity and its relationship to treatment response are still poorly understood. Recently, new light has been shed on the mechanism-of-action of anthracyclines, which may help elucidate new mechanisms of chemoresistance. Accumulating data suggest that anthracyclines mediate their anticancer activity not only by direct cytotoxic effects but also through activation of adaptive antitumor immune responses (6) by inducing a type of tumor cell death that is "immunogenic" (7-10). In mice, chemotherapy with anthracyclines requires IFN-γ-producing CD8 + T cells for optimal activity. This finding is further supported by correlative clinical studies that report that high intratumoral levels of I...

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Section: Discussionmentioning

confidence: 69%

CD73 promotes anthracycline resistance and poor prognosis in triple negative breast cancer

Loi

Pommey

Haibe‐Kains

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

416

392

View full text Add to dashboard Cite

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“…19,42,48,49 The mRNA expression and methylation status of NT5E have been correlated with the clinical survival outcome 19,42 in breast cancer patients. Antibody therapy against NT5E was suggested as a possible treatment in breast cancer 14 and has been shown to suppress metastasis 50 and tumor angiogenesis.…”

Section: ■ Discussionmentioning

confidence: 99%

A Systems Oncology Approach Identifies NT5E as a Key Metabolic Regulator in Tumor Cells and Modulator of Platinum Sensitivity

et al. 2015

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Altered metabolism in tumor cells is required for rapid proliferation but also can influence other phenotypes that affect clinical outcomes such as metastasis and sensitivity to chemotherapy. Here, a genome-wide association study (GWAS)-guided integration of NCI-60 transcriptome and metabolome data identified ecto-5′-nucleotidase (NT5E or CD73) as a major determinant of metabolic phenotypes in cancer cells. NT5E expression and associated metabolome variations were also correlated with sensitivity to several chemotherapeutics including platinum-based treatment. NT5E mRNA levels were observed to be elevated in cells upon in vitro and in vivo acquisition of platinum resistance in ovarian cancer cells, and specific targeting of NT5E increased tumor cell sensitivity to platinum. We observed that tumor NT5E levels were prognostic for outcomes in ovarian cancer and were elevated after treatment with platinum, supporting the translational relevance of our findings. In this work, we integrated and analyzed a plethora of public data, demonstating the merit of such a systems oncology approach for the discovery of novel players in cancer biology and therapy. We experimentally validated the main findings of the NT5E gene being involved in both intrinsic and acquired resistance to platinum-based drugs. We propose that the efficacy of conventional chemotherapy could be improved by NT5E inhibition and that NT5E expression may be a useful prognostic and predictive clinical biomarker.

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“…In total, this approach identified six targets: EGFR, B-CAM, CD44, CD73, CD71 and HER2. All of these have previously been implicated in cancer progression, with the least validation associated with CD73 [13,14]. It must be noted that the MDA-MB-231 cell line is described as HER2 negative, and it does not amplify or overexpress HER2.…”

Section: Discussionmentioning

confidence: 99%

Combining phenotypic and proteomic approaches to identify membrane targets in a ‘triple negative’ breast cancer cell type

Rust¹,

Guillard²,

Sachsenmeier³

et al. 2013

Molecular Cancer

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BackgroundThe continued discovery of therapeutic antibodies, which address unmet medical needs, requires the continued discovery of tractable antibody targets. Multiple protein-level target discovery approaches are available and these can be used in combination to extensively survey relevant cell membranomes. In this study, the MDA-MB-231 cell line was selected for membranome survey as it is a ‘triple negative’ breast cancer cell line, which represents a cancer subtype that is aggressive and has few treatment options.MethodsThe MDA-MB-231 breast carcinoma cell line was used to explore three membranome target discovery approaches, which were used in parallel to cross-validate the significance of identified antigens. A proteomic approach, which used membrane protein enrichment followed by protein identification by mass spectrometry, was used alongside two phenotypic antibody screening approaches. The first phenotypic screening approach was based on hybridoma technology and the second was based on phage display technology. Antibodies isolated by the phenotypic approaches were tested for cell specificity as well as internalisation and the targets identified were compared to each other as well as those identified by the proteomic approach. An anti-CD73 antibody derived from the phage display-based phenotypic approach was tested for binding to other ‘triple negative’ breast cancer cell lines and tested for tumour growth inhibitory activity in a MDA-MB-231 xenograft model.ResultsAll of the approaches identified multiple cell surface markers, including integrins, CD44, EGFR, CD71, galectin-3, CD73 and BCAM, some of which had been previously confirmed as being tractable to antibody therapy. In total, 40 cell surface markers were identified for further study. In addition to cell surface marker identification, the phenotypic antibody screening approaches provided reagent antibodies for target validation studies. This is illustrated using the anti-CD73 antibody, which bound other ‘triple negative’ breast cancer cell lines and produced significant tumour growth inhibitory activity in a MDA-MB-231 xenograft model.ConclusionsThis study has demonstrated that multiple methods are required to successfully analyse the membranome of a desired cell type. It has also successfully demonstrated that phenotypic antibody screening provides a mechanism for rapidly discovering and evaluating antibody tractable targets, which can significantly accelerate the therapeutic discovery process.

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NT5E CpG island methylation is a favourable breast cancer biomarker

Cited by 36 publications

References 30 publications

CD73 promotes anthracycline resistance and poor prognosis in triple negative breast cancer

CD73 promotes anthracycline resistance and poor prognosis in triple negative breast cancer

A Systems Oncology Approach Identifies NT5E as a Key Metabolic Regulator in Tumor Cells and Modulator of Platinum Sensitivity

Combining phenotypic and proteomic approaches to identify membrane targets in a ‘triple negative’ breast cancer cell type

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