Mitochondrial “power” drives tamoxifen resistance : NQO1 and GCLC are new therapeutic targets in breast cancer

Fiorillo, M; Sotgia, F; Sisci, D; Cappello, AR; Lisanti, MP

Abstract

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 tamoxifenresistance
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).

Citation

Fiorillo, M., Sotgia, F., Sisci, D., Cappello, A., & Lisanti, M. (2017). Mitochondrial “power” drives tamoxifen resistance : NQO1 and GCLC are new therapeutic targets in breast cancer. Oncotarget, 2017(8), 20309-20327. https://doi.org/10.18632/oncotarget.15852

• Journal Article Type: Article
• Acceptance Date: Feb 1, 2017
• Online Publication Date: Mar 2, 2017
• Publication Date: Mar 2, 2017
• Deposit Date: Mar 31, 2017
• Publicly Available Date: Mar 31, 2017
• Journal: Oncotarget
• Electronic ISSN: 1949-2553
• Publisher: Impact Journals
• Volume: 2017
• Issue: 8
• Pages: 20309-20327
• DOI: https://doi.org/10.18632/oncotarget.15852
• Publisher URL: http://dx.doi.org/10.18632/oncotarget.15852
• Related Public URLs: http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget