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

Helen Sadik, Preethi Korangath, Nguyen K. Nguyen, Balazs Gyorffy, Rakesh Kumar, Mohammad Hedayati, Wei Wen Teo, Sunju Park, Hardik Panday, Teresa Gonzalez Munoz, Otilia Menyhart, Nilay Shah, Raj K. Pandita, Jenny C. Chang, Theodore DeWeese, Howard Y. Chang, Tej K. Pandita, Saraswati Sukumar

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4443-4456
Number of pages14
JournalCancer Research
Volume76
Issue number15
DOIs
StatePublished - Aug 1 2016

Fingerprint

DNA Repair
DNA Damage
Homologous Recombination
Drug Resistance
Breast Neoplasms
Drug Therapy
Cyclin-Dependent Kinases
RNA Polymerase II
Carboplatin
Paclitaxel
DNA Replication
S Phase
Estrogen Receptors
Doxorubicin
Cultured Cells
Cell Survival
Apoptosis
Neoplasm Metastasis
Recurrence
Survival

ASJC Scopus subject areas

  • Medicine(all)
  • Oncology
  • Cancer Research

Cite this

HOXC10 expression supports the development of chemotherapy resistance by fine tuning DNA repair in breast cancer cells. / Sadik, Helen; Korangath, Preethi; Nguyen, Nguyen K.; Gyorffy, Balazs; Kumar, Rakesh; Hedayati, Mohammad; Teo, Wei Wen; Park, Sunju; Panday, Hardik; Munoz, Teresa Gonzalez; Menyhart, Otilia; Shah, Nilay; Pandita, Raj K.; Chang, Jenny C.; DeWeese, Theodore; Chang, Howard Y.; Pandita, Tej K.; Sukumar, Saraswati.

In: Cancer Research, Vol. 76, No. 15, 01.08.2016, p. 4443-4456.

Research output: Contribution to journalArticle

Sadik, H, Korangath, P, Nguyen, NK, Gyorffy, B, Kumar, R, Hedayati, M, Teo, WW, Park, S, Panday, H, Munoz, TG, Menyhart, O, Shah, N, Pandita, RK, Chang, JC, DeWeese, T, Chang, HY, Pandita, TK & Sukumar, S 2016, 'HOXC10 expression supports the development of chemotherapy resistance by fine tuning DNA repair in breast cancer cells', Cancer Research, vol. 76, no. 15, pp. 4443-4456. https://doi.org/10.1158/0008-5472.CAN-16-0774
Sadik, Helen ; Korangath, Preethi ; Nguyen, Nguyen K. ; Gyorffy, Balazs ; Kumar, Rakesh ; Hedayati, Mohammad ; Teo, Wei Wen ; Park, Sunju ; Panday, Hardik ; Munoz, Teresa Gonzalez ; Menyhart, Otilia ; Shah, Nilay ; Pandita, Raj K. ; Chang, Jenny C. ; DeWeese, Theodore ; Chang, Howard Y. ; Pandita, Tej K. ; Sukumar, Saraswati. / HOXC10 expression supports the development of chemotherapy resistance by fine tuning DNA repair in breast cancer cells. In: Cancer Research. 2016 ; Vol. 76, No. 15. pp. 4443-4456.
@article{7f6ede18540347e79c0c6cea75b7cd7e,
title = "HOXC10 expression supports the development of chemotherapy resistance by fine tuning DNA repair in breast cancer cells",
abstract = "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.",
author = "Helen Sadik and Preethi Korangath and Nguyen, {Nguyen K.} and Balazs Gyorffy and Rakesh Kumar and Mohammad Hedayati and Teo, {Wei Wen} and Sunju Park and Hardik Panday and Munoz, {Teresa Gonzalez} and Otilia Menyhart and Nilay Shah and Pandita, {Raj K.} and Chang, {Jenny C.} and Theodore DeWeese and Chang, {Howard Y.} and Pandita, {Tej K.} and Saraswati Sukumar",
year = "2016",
month = "8",
day = "1",
doi = "10.1158/0008-5472.CAN-16-0774",
language = "English (US)",
volume = "76",
pages = "4443--4456",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "15",

}

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

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.

UR - http://www.scopus.com/inward/record.url?scp=84982720852&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84982720852&partnerID=8YFLogxK

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 - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 15

ER -