HOXC10 expression supports the development of chemotherapy resistance by fine tuning DNA repair in breast cancer cells

Sadik, H. and Korangath, P. and Nguyen, N. K. and Győrffy, Balázs and Kumar, R. (2016) HOXC10 expression supports the development of chemotherapy resistance by fine tuning DNA repair in breast cancer cells. CANCER RESEARCH, 76 (15). pp. 4443-4456. ISSN 0008-5472

[img] Text
Restricted to Repository staff only

Download (1MB) | Request a copy


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. ©2016 AACR.

Item Type: Article
Uncontrolled Keywords: recurrence free survival; PROTEIN SECRETION; protein protein interaction; PROTEIN FUNCTION; protein expression; priority journal; overall survival; nonhuman; MOUSE; human tissue; human; Homologous recombination; enzyme phosphorylation; enzyme inhibition; enzyme activation; DNA Replication; DNA Repair; DNA damage checkpoint; distant metastasis; controlled study; Cell Survival; cancer resistance; breast cancer; binding affinity; ARTICLE; APOPTOSIS; animal model; animal experiment; unclassified drug; rna polymerase; HOXC10 protein; Hox protein; cyclin dependent kinase 7
Subjects: R Medicine / orvostudomány > RC Internal medicine / belgyógyászat > RC0254 Neoplasms. Tumors. Oncology (including Cancer) / daganatok, tumorok, onkológia
Depositing User: MTMT SWORD
Date Deposited: 26 Jan 2017 15:37
Last Modified: 26 Jan 2017 15:37

Actions (login required)

Edit Item Edit Item