Article

Glutamine Sensitivity Analysis Identifies the xCT Antiporter as a Common Triple-Negative Breast Tumor Therapeutic Target

UCSF/Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94115, USA. Electronic address: .
Cancer cell (Impact Factor: 23.89). 10/2013; 24(4). DOI: 10.1016/j.ccr.2013.08.020
Source: PubMed

ABSTRACT A handful of tumor-derived cell lines form the mainstay of cancer therapeutic development, yielding drugs with an impact typically measured as months to disease progression. To develop more effective breast cancer therapeutics and more readily understand their clinical impact, we constructed a functional metabolic portrait of 46 independently derived breast cell lines. Our analysis of glutamine uptake and dependence identified a subset of triple-negative samples that are glutamine auxotrophs. Ambient glutamine indirectly supports environmental cystine acquisition via the xCT antiporter, which is expressed on one-third of triple-negative tumors in vivo. xCT inhibition with the clinically approved anti-inflammatory sulfasalazine decreases tumor growth, revealing a therapeutic target in breast tumors of poorest prognosis and a lead compound for rapid, effective drug development.

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    • "Increased reliance on xCT for import of cysteine for glutathione synthesis also suggests that targeting of this receptor will provide greater therapeutic margins than direct inhibition of glutathione synthesis that would be expected to result in wide-ranging toxicities [32]. Thus, xCT is considered an attractive target for cancer [28] [29]. Activation of oncogenes reprogram cancer cells toward aerobic glycolysis to support their proliferation and growth, a phenomenon known as the Warburg effect [2]. "
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    • "RPPA analysis confirmed that high expression of SLC1A5 is associated with basal-like and luminal B types of BCa, as well poorer responsiveness to therapy, whereas low SLC1A5 expression coincided with reactive, luminal type tumors. Along these lines, tumors more dependent on Gln, such as triple-negative BCa cells (Timmerman et al., 2013) and melanoma cells (Filipp et al., 2012), could benefit from therapies that target Gln-pathway components in combination with other therapies. Our data also show that RNF5-medi- ated control of Gln carrier proteins does not function in all BCa (E) MDA-MB-231 cells transfected with indicated constructs were incubated with 2.5 mg/ml BFA for 24 hr, stained with Annexin-V-EGFP and PI, and analyzed by FACS. "
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    • "Breast cancer (BC) is a heterogeneous disease that can be classified into estrogen receptor a-positive (ERa + ) and HER2 + tumors as well as triple-negative (TN) tumors, which do not express high levels of these or the progesterone receptors (Prat & Perou, 2011). TNBCs include two major subtypes: basal-like, expressing basal-cell markers such as cytokeratin 14, and claudin-low/mesenchymal-like, expressing low levels of tight junction proteins including certain claudins and E-cadherin, and high levels of genes associated with epithelial-to-mesenchymal transition (EMT) (Prat et al, 2010; Lehmann et al, 2011; Timmerman et al, 2013). Interest in the latter tumors is driven by observations that following conventional therapy , residual tumors exhibit features of cancer stem cells and EMT (Mani et al, 2008; Creighton et al, 2009; Guo et al, 2012). "
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