Mitochondrial “power” drives tamoxifen resistance: NQO1 and GCLC are new therapeutic targets in breast cancer
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Marco Fiorillo1,2, Federica Sotgia3, Diego Sisci1, Anna Rita Cappello1 and Michael P. Lisanti3
1 The Department of Pharmacy, Health and Nutritional Sciences, The University of Calabria, Cosenza, 87100, Italy
2 The Paterson Institute, University of Manchester, Withington, M20 4BX, United Kingdom
3 Translational Medicine, School of Environment and Life Sciences, Biomedical Research Centre, University of Salford, Greater Manchester, M5 4WT, United Kingdom
Anna Rita Cappello, email:
Michael P. Lisanti, email:
Keywords: tamoxifen resistance; endocrine therapy; mitochondria; drug resistance; breast cancer
Received: January 17, 2017 Accepted: February 01, 2017 Published: March 02, 2017
Here, we identified two new molecular targets, which are functionally sufficient to metabolically confer the tamoxifen-resistance phenotype in human breast cancer cells. Briefly, ~20 proteins were first selected as potential candidates, based on unbiased proteomics analysis, using tamoxifen-resistant cell lines. Then, the cDNAs of the most promising candidates were systematically transduced into MCF-7 cells. Remarkably, NQO1 and GCLC were both functionally sufficient to autonomously confer a tamoxifen-resistant metabolic phenotype, characterized by i) increased mitochondrial biogenesis, ii) increased ATP production and iii) reduced glutathione levels. Thus, we speculate that pharmacological inhibition of NQO1 and GCLC may be new therapeutic strategies for overcoming tamoxifen-resistance in breast cancer patients. In direct support of this notion, we demonstrate that treatment with a known NQO1 inhibitor (dicoumarol) is indeed sufficient to revert the tamoxifen-resistance phenotype. As such, these findings could have important translational significance for the prevention of tumor recurrence in ER(+) breast cancers, which is due to an endocrine resistance phenotype. Importantly, we also show here that NQO1 has significant prognostic value as a biomarker for the prediction of tumor recurrence. More specifically, higher levels of NQO1 mRNA strongly predict patient relapse in high-risk ER(+) breast cancer patients receiving endocrine therapy (mostly tamoxifen; H.R. > 2.15; p = 0.007).
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