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 - Funding Information:
We wish to thank the nursing staff of the Tawam Hospital-Johns Hopkins Medicine Breast Care Center (Al Ain, United Arab Emirates) for their invaluable assistance in coordinating the collection of patient samples. We also thank Phani Gummadidala and Brian Silverstrim for technical support (University of Vermont). This work was funded by a grant from the Terry Fox Fund for Cancer Research (M.J. Fernández-Cabezudo and B.K. al-Ramadi), NIH grant R01 DE022772 (B.C. Christensen), NIH grant R21 CA127099 (M. Rincon), NIH grant R21 AI110016 (M. Rincon), and Lake Champlain Cancer Center Research Organization (LLCRO) (M. Rincon). Bioinformatic analyses were supported in part by the Biostatistics/Bioinformatics Shared Resources of Colorado's NIH/NCI Cancer Center (support grant P30 CA046934).
Funding Information:
We wish to thank the nursing staff of the Tawam Hospital-Johns Hopkins Medicine Breast Care Center (Al Ain, United Arab Emirates) for their invaluable assistance in coordinating the collection of patient samples. We also thank Phani Gummadidala and Brian Silverstrim for technical support (University of Vermont). This work was funded by a grant from the Terry Fox Fund for Cancer Research (M.J. Fernández-Cabezudo and B.K. al-Ramadi), NIH grant R01 DE022772 (B.C. Christensen), NIH grant R21 CA127099 (M. Rin- con), NIH grant R21 AI110016 (M. Rincon), and Lake Champlain Cancer Center Research Organization (LLCRO) (M. Rincon). Bioinformatic analyses were supported in part by the Biostatistics/Bioinformatics Shared Resources of Colorado’s NIH/NCI Cancer Center (support grant P30 CA046934).
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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UR - http://www.scopus.com/inward/citedby.url?scp=85026857104&partnerID=8YFLogxK
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 -