Deficiency of mitochondrial modulator MCJ promotes chemoresistance in breast cancer.
Fernández-Cabezudo, MJ; Faour, I; Jones, K; Champagne, DP; Jaloudi, MA; Mohamed, YA; Bashir, G; Almarzooqi, S; Albawardi, A; Hashim, MJ; Roberts, TS; El-Salhat, H; El-Taji, H; Kassis, A; O'Sullivan, DE; Christensen, BC; DeGregori, J; Al-Ramadi, BK; Rincon, M
JCI Insight
1
2015
Mostrar resumen
Despite major advances in early detection and prognosis, chemotherapy resistance is a major hurdle in the battle against breast cancer. Identifying predictive markers and understanding the mechanisms are key steps to overcoming chemoresistance. Methylation-controlled J protein (MCJ, also known as DNAJC15) is a negative regulator of mitochondrial respiration and has been associated with chemotherapeutic drug sensitivity in cancer cell lines. Here we show, in a retrospective study of a large cohort of breast cancer patients, that low MCJ expression in breast tumors predicts high risk of relapse in patients treated with chemotherapy; however, MCJ expression does not correlate with response to endocrine therapy. In a prospective study in breast cancer patients undergoing neoadjuvant therapy, low MCJ expression also correlates with poor clinical response to chemotherapy and decreased disease-free survival. Using MCJ-deficient mice, we demonstrate that lack of MCJ is sufficient to induce mammary tumor chemoresistance in vivo. Thus, loss of expression of this endogenous mitochondrial modulator in breast cancer promotes the development of chemoresistance. | 27275014
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Methylation-controlled J protein promotes c-Jun degradation to prevent ABCB1 transporter expression.
Hatle, KM; Neveu, W; Dienz, O; Rymarchyk, S; Barrantes, R; Hale, S; Farley, N; Lounsbury, KM; Bond, JP; Taatjes, D; Rincón, M
Mol Cell Biol
27
2952-66
2007
Mostrar resumen
Methylation-controlled J protein (MCJ) is a newly identified member of the DnaJ family of cochaperones. Hypermethylation-mediated transcriptional silencing of the MCJ gene has been associated with increased chemotherapeutic resistance in ovarian cancer. However, the biology and function of MCJ remain unknown. Here we show that MCJ is a type II transmembrane cochaperone localized in the Golgi network and present only in vertebrates. MCJ is expressed in drug-sensitive breast cancer cells but not in multidrug-resistant cells. The inhibition of MCJ expression increases resistance to specific drugs by inducing expression of the ABCB1 drug transporter that prevents intracellular drug accumulation. The induction of ABCB1 gene expression is mediated by increased levels of c-Jun due to an impaired degradation of this transcription factor in the absence of MCJ. Thus, MCJ is required in these cells to prevent c-Jun-mediated expression of ABCB1 and maintain drug response. | 17283040
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