Deficiency of mitochondrial modulator MCJ promotes chemoresistance in breast cancer.
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.
Department of Biochemistry, College of Medicine & Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates.
Maria J
MJ
Fernández-Cabezudo
Department of Surgery, Tawam Hospital-Johns Hopkins Medicine, Al-Ain, United Arab Emirates.
Issam
I
Faour
Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, Colorado, USA.
Kenneth
K
Jones
Department of Medicine/Immunobiology Division, University of Vermont, Burlington, Vermont, USA.
Devin P
DP
Champagne
Department of Medical Oncology, Tawam Hospital-Johns Hopkins Medicine, Al-Ain, United Arab Emirates.
Mohammed A
MA
Jaloudi
Department of Medical Microbiology & Immunology, United Arab Emirates University, Al-Ain, United Arab Emirates.
Yassir A
YA
Mohamed
Department of Medical Microbiology & Immunology, United Arab Emirates University, Al-Ain, United Arab Emirates.
Ghada
G
Bashir
Department of Pathology, United Arab Emirates University, Al-Ain, United Arab Emirates.
Saeeda
S
Almarzooqi
Department of Pathology, United Arab Emirates University, Al-Ain, United Arab Emirates.
Alia
A
Albawardi
Family Medicine, College of Medicine & Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates.
M Jawad
MJ
Hashim
Department of Medicine/Immunobiology Division, University of Vermont, Burlington, Vermont, USA.
Thomas S
TS
Roberts
Department of Surgery, Tawam Hospital-Johns Hopkins Medicine, Al-Ain, United Arab Emirates.
Haytham
H
El-Salhat
Department of Surgery, Tawam Hospital-Johns Hopkins Medicine, Al-Ain, United Arab Emirates.
Hakam
H
El-Taji
Department of Clinical Imaging, Tawam Hospital-Johns Hopkins Medicine, Al-Ain, United Arab Emirates.
Adnan
A
Kassis
Departments of Epidemiology, Pharmacology and Toxicology, and Community and Family Medicine, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA.
Dylan E
DE
O'Sullivan
Departments of Epidemiology, Pharmacology and Toxicology, and Community and Family Medicine, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA.
Brock C
BC
Christensen
Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, Colorado, USA.
James
J
DeGregori
Department of Medical Microbiology & Immunology, United Arab Emirates University, Al-Ain, United Arab Emirates.
Basel K
BK
Al-Ramadi
Department of Medicine/Immunobiology Division, University of Vermont, Burlington, Vermont, USA.
Mercedes
M
Rincon