HOXC10 Expression Supports the Development of Chemotherapy Resistance by Fine Tuning DNA Repair in Breast Cancer Cells.
Development of drug resistance is a major factor limiting the continued success of cancer chemotherapy. To overcome drug resistance, understanding the underlying mechanism(s) is essential. We found that HOXC10 is overexpressed in primary carcinomas of the breast, and even more significantly in distant metastasis arising after failed chemotherapy. High HOXC10 expression correlates with shorter recurrence-free and overall survival in patients with estrogen receptor-negative breast cancer undergoing chemotherapy. We found that HOXC10 promotes survival in cells treated with doxorubicin, paclitaxel, or carboplatin by suppressing apoptosis and upregulating NF-κB Overexpressed HOXC10 increases S-phase-specific DNA damage repair by homologous recombination (HR) and checkpoint recovery in cells at three important phases. For double-strand break repair, HOXC10 recruits HR proteins at sites of DNA damage. It enhances resection and lastly, it resolves stalled replication forks, leading to initiation of DNA replication following DNA damage. We show that HOXC10 facilitates, but is not directly involved in DNA damage repair mediated by HR. HOXC10 achieves integration of these functions by binding to, and activating cyclin-dependent kinase, CDK7, which regulates transcription by phosphorylating the carboxy-terminal domain of RNA polymerase II. Consistent with these findings, inhibitors of CDK7 reverse HOXC10-mediated drug resistance in cultured cells. Blocking HOXC10 function, therefore, presents a promising new strategy to overcome chemotherapy resistance in breast cancer. Cancer Res; 76(15); 4443-56. ©2016 AACR.
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Helen
H
Sadik
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Preethi
P
Korangath
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Nguyen K
NK
Nguyen
MTA TTK Lendület Cancer Biomarker Research Group, Budapest, Hungary. 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary.
Balazs
B
Gyorffy
Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas.
Rakesh
R
Kumar
Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Mohammad
M
Hedayati
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Wei Wen
WW
Teo
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Sunju
S
Park
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Hardik
H
Panday
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Teresa Gonzalez
TG
Munoz
MTA TTK Lendület Cancer Biomarker Research Group, Budapest, Hungary. 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary.
Otilia
O
Menyhart
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Nilay
N
Shah
Department of Radiation Oncology, The Houston Methodist Research Institute, Houston, Texas.
Raj K
RK
Pandita
Methodist Cancer Center, The Houston Methodist Research Institute, Houston, Texas.
Jenny C
JC
Chang
Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Theodore
T
DeWeese
Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California.
Howard Y
HY
Chang
Department of Radiation Oncology, The Houston Methodist Research Institute, Houston, Texas. saras@jhmi.edu tpandita@houstonmethodist.org.
Tej K
TK
Pandita
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. saras@jhmi.edu tpandita@houstonmethodist.org.
Saraswati
S
Sukumar
D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D004260:DNA Repair; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans
C410304:HOXC10 protein, human; D018398:Homeodomain Proteins