TY - JOUR
T1 - Deficiency of mitochondrial modulator MCJ promotes chemoresistance in breast cancer
AU - Fernández-Cabezudo, Maria J.
AU - Faour, Issam
AU - Jones, Kenneth
AU - Champagne, Devin P.
AU - Jaloudi, Mohammed A.
AU - Mohamed, Yassir A.
AU - Bashir, Ghada
AU - Almarzooqi, Saeeda
AU - Albawardi, Alia
AU - Hashim, M. Jawad
AU - Roberts, Thomas S.
AU - El-Salhat, Haytham
AU - El-Taji, Hakam
AU - Kassis, Adnan
AU - O'Sullivan, Dylan E.
AU - Christensen, Brock C.
AU - DeGregori, James
AU - Al-Ramadi, Basel K.
AU - Rincon, Mercedes
N1 - Publisher Copyright:
© 2016 American Society for Clinical Investigation. All rights reserved.
PY - 2016/5/19
Y1 - 2016/5/19
N2 - 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.
AB - 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.
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U2 - 10.1172/jci.insight.86873
DO - 10.1172/jci.insight.86873
M3 - Article
AN - SCOPUS:85026857104
SN - 2379-3708
VL - 1
JO - JCI insight
JF - JCI insight
IS - 7
M1 - e86873
ER -