TY - JOUR
T1 - HOXC10 expression supports the development of chemotherapy resistance by fine tuning DNA repair in breast cancer cells
AU - Sadik, Helen
AU - Korangath, Preethi
AU - Nguyen, Nguyen K.
AU - Gyorffy, Balazs
AU - Kumar, Rakesh
AU - Hedayati, Mohammad
AU - Teo, Wei Wen
AU - Park, Sunju
AU - Panday, Hardik
AU - Munoz, Teresa Gonzalez
AU - Menyhart, Otilia
AU - Shah, Nilay
AU - Pandita, Raj K.
AU - Chang, Jenny C.
AU - DeWeese, Theodore
AU - Chang, Howard Y.
AU - Pandita, Tej K.
AU - Sukumar, Saraswati
N1 - Funding Information:
We thank Dr. Joel L. Pomerantz for providing us their responsive reporter plasmids NF-kB-luc, Dr. Amadeo M Parissenti for the drug-resistant MCF7 cell lines, and Dr. Alan Rein for reviewing the article. This work was supported by funding from the DOD-BCRP BC093970 (H. Sadik), NCI-P50-CA88843 and P30-CA006973 (S. Sukumar) and NIH grants CA129537, CA154320, and GM109768 (T.K. Pandita). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
©2016 AACR.
PY - 2016/8/1
Y1 - 2016/8/1
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-16-0774
DO - 10.1158/0008-5472.CAN-16-0774
M3 - Article
C2 - 27302171
AN - SCOPUS:84982720852
VL - 76
SP - 4443
EP - 4456
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 15
ER -