Poly-ADP-Ribosylation of Estrogen Receptor-Alpha by PARP1 mediates antiestrogen resistance in human breast cancer cells

Nicholas Pulliam, Jessica Tang, Weini Wang, Fang Fang, Riddhi Sood, Heather O'Hagan, Kathy Miller, Robert Clarke, Kenneth Nephew

Research output: Contribution to journalArticle

Abstract

Therapeutic targeting of estrogen receptor-α (ERα) by the anti-estrogen tamoxifen is standard of care for premenopausal breast cancer patients and remains a key component of treatment strategies for postmenopausal patients. While tamoxifen significantly increases overall survival, tamoxifen resistance remains a major limitation despite continued expression of ERα in resistant tumors. Previous reports have described increased oxidative stress in tamoxifen resistant versus sensitive breast cancer and a role for PARP1 in mediating oxidative damage repair. We hypothesized that PARP1 activity mediated tamoxifen resistance in ERα-positive breast cancer and that combining the antiestrogen tamoxifenwith a PARP1 inhibitor (PARPi)would sensitize tamoxifen resistant cells to tamoxifen therapy. In tamoxifen-resistant vs. -sensitive breast cancer cells, oxidative stress and PARP1 overexpression were increased. Furthermore, differential PARylation of ERα was observed in tamoxifen-resistant versus -sensitive cells, and ERα PARylation was increased by tamoxifen treatment. Loss of ERα PARylation following treatment with a PARP inhibitor (talazoparib) augmented tamoxifen sensitivity and decreased localization of both ERα and PARP1 to ERα-target genes. Co-administration of talazoparib plus tamoxifen increased DNA damage accumulation and decreased cell survival in a dose-dependent manner. The ability of PARPi to overcome tamoxifen resistance was dependent on ERα, as lack of ERα-mediated estrogen signaling expression and showed no response to tamoxifen-PARPi treatment. These results correlate ERα PARylationwith tamoxifen resistance and indicate a novelmechanism-based approach to overcome tamoxifen resistance in ER+ breast cancer.

Original languageEnglish (US)
Article number43
JournalCancers
Volume11
Issue number1
DOIs
StatePublished - Jan 1 2019

Fingerprint

Estrogen Receptor Modulators
Estrogen Receptor alpha
Tamoxifen
Adenosine Diphosphate
Estrogen Receptors
Breast Neoplasms
Estrogens
Oxidative Stress
Therapeutics
Standard of Care

Keywords

  • Antiestrogen resistance
  • Breast cancer
  • Estrogen receptor
  • PARP inhibitor
  • Tamoxifen

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Poly-ADP-Ribosylation of Estrogen Receptor-Alpha by PARP1 mediates antiestrogen resistance in human breast cancer cells. / Pulliam, Nicholas; Tang, Jessica; Wang, Weini; Fang, Fang; Sood, Riddhi; O'Hagan, Heather; Miller, Kathy; Clarke, Robert; Nephew, Kenneth.

In: Cancers, Vol. 11, No. 1, 43, 01.01.2019.

Research output: Contribution to journalArticle

Pulliam, Nicholas ; Tang, Jessica ; Wang, Weini ; Fang, Fang ; Sood, Riddhi ; O'Hagan, Heather ; Miller, Kathy ; Clarke, Robert ; Nephew, Kenneth. / Poly-ADP-Ribosylation of Estrogen Receptor-Alpha by PARP1 mediates antiestrogen resistance in human breast cancer cells. In: Cancers. 2019 ; Vol. 11, No. 1.
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abstract = "Therapeutic targeting of estrogen receptor-α (ERα) by the anti-estrogen tamoxifen is standard of care for premenopausal breast cancer patients and remains a key component of treatment strategies for postmenopausal patients. While tamoxifen significantly increases overall survival, tamoxifen resistance remains a major limitation despite continued expression of ERα in resistant tumors. Previous reports have described increased oxidative stress in tamoxifen resistant versus sensitive breast cancer and a role for PARP1 in mediating oxidative damage repair. We hypothesized that PARP1 activity mediated tamoxifen resistance in ERα-positive breast cancer and that combining the antiestrogen tamoxifenwith a PARP1 inhibitor (PARPi)would sensitize tamoxifen resistant cells to tamoxifen therapy. In tamoxifen-resistant vs. -sensitive breast cancer cells, oxidative stress and PARP1 overexpression were increased. Furthermore, differential PARylation of ERα was observed in tamoxifen-resistant versus -sensitive cells, and ERα PARylation was increased by tamoxifen treatment. Loss of ERα PARylation following treatment with a PARP inhibitor (talazoparib) augmented tamoxifen sensitivity and decreased localization of both ERα and PARP1 to ERα-target genes. Co-administration of talazoparib plus tamoxifen increased DNA damage accumulation and decreased cell survival in a dose-dependent manner. The ability of PARPi to overcome tamoxifen resistance was dependent on ERα, as lack of ERα-mediated estrogen signaling expression and showed no response to tamoxifen-PARPi treatment. These results correlate ERα PARylationwith tamoxifen resistance and indicate a novelmechanism-based approach to overcome tamoxifen resistance in ER+ breast cancer.",
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