Mechanism of Telapristone Acetate (CDB4124) on Progesterone Receptor Action in Breast Cancer Cells

Batzaya Davaadelger, Alina R. Murphy, Susan E. Clare, Oukseub Lee, Seema A. Khan, J. Julie Kim

Research output: Contribution to journalArticle

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Abstract

Progesterone is a steroid hormone that plays an important role in the breast. Progesterone exerts its action through binding to progesterone receptor (PR), a transcription factor. Deregulation of the progesterone signaling pathway is implicated in the formation, development, and progression of breast cancer. Next-generation selective progesterone receptor modulators (SPRMs) have potent antiprogestin activity and are selective for PR, reducing the off-target effects on other nuclear receptors. To date, there is limited information on how the newer generation of SPRMs, specifically telapristone acetate (TPA), affect PR function at the molecular level. In this study, T47D breast cancer cells were used to investigate the molecular mechanism by which TPA antagonizes PR action. Global profiling of the PR cistrome and interactome was done with chromatin immunoprecipitation sequencing (ChIP-seq) and rapid immunoprecipitation mass spectrometry. Validation studies were done on key genes and interactions. Our results demonstrate that treatment with the progestin (R5020) alone resulted in robust PR recruitment to the chromatin, and addition of TPA reduced PR recruitment globally. TPA significantly changed coregulator recruitment to PR compared with R5020. Upon conservative analysis, three proteins (TRPS1, LASP1, and AP1G1) were identified in the R5020+TPA-treated group. Silencing TRPS1 with small interfering RNA increased PR occupancy to the known PR regulatory regions and attenuated the inhibition of gene expression after TPA treatment. TRPS1 silencing alleviated the inhibition of proliferation by TPA. In conclusion, TPA decreases PR occupancy on chromatin and recruits coregulators such as TRPS1 to the PR complex, thereby regulating PR target gene expression and associated cellular responses.

Original languageEnglish (US)
Pages (from-to)3581-3595
Number of pages15
JournalEndocrinology
Volume159
Issue number10
DOIs
StatePublished - Oct 1 2018

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Progesterone Receptors
Breast Neoplasms
Promegestone
Progesterone
telapristone acetate
Chromatin
Gene Expression
Chromatin Immunoprecipitation
Validation Studies
Nucleic Acid Regulatory Sequences
Progestins
Cytoplasmic and Nuclear Receptors
Immunoprecipitation
Small Interfering RNA
Mass Spectrometry
Breast
Transcription Factors

ASJC Scopus subject areas

  • Endocrinology

Cite this

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title = "Mechanism of Telapristone Acetate (CDB4124) on Progesterone Receptor Action in Breast Cancer Cells",
abstract = "Progesterone is a steroid hormone that plays an important role in the breast. Progesterone exerts its action through binding to progesterone receptor (PR), a transcription factor. Deregulation of the progesterone signaling pathway is implicated in the formation, development, and progression of breast cancer. Next-generation selective progesterone receptor modulators (SPRMs) have potent antiprogestin activity and are selective for PR, reducing the off-target effects on other nuclear receptors. To date, there is limited information on how the newer generation of SPRMs, specifically telapristone acetate (TPA), affect PR function at the molecular level. In this study, T47D breast cancer cells were used to investigate the molecular mechanism by which TPA antagonizes PR action. Global profiling of the PR cistrome and interactome was done with chromatin immunoprecipitation sequencing (ChIP-seq) and rapid immunoprecipitation mass spectrometry. Validation studies were done on key genes and interactions. Our results demonstrate that treatment with the progestin (R5020) alone resulted in robust PR recruitment to the chromatin, and addition of TPA reduced PR recruitment globally. TPA significantly changed coregulator recruitment to PR compared with R5020. Upon conservative analysis, three proteins (TRPS1, LASP1, and AP1G1) were identified in the R5020+TPA-treated group. Silencing TRPS1 with small interfering RNA increased PR occupancy to the known PR regulatory regions and attenuated the inhibition of gene expression after TPA treatment. TRPS1 silencing alleviated the inhibition of proliferation by TPA. In conclusion, TPA decreases PR occupancy on chromatin and recruits coregulators such as TRPS1 to the PR complex, thereby regulating PR target gene expression and associated cellular responses.",
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Mechanism of Telapristone Acetate (CDB4124) on Progesterone Receptor Action in Breast Cancer Cells. / Davaadelger, Batzaya; Murphy, Alina R.; Clare, Susan E.; Lee, Oukseub; Khan, Seema A.; Kim, J. Julie.

In: Endocrinology, Vol. 159, No. 10, 01.10.2018, p. 3581-3595.

Research output: Contribution to journalArticle

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T1 - Mechanism of Telapristone Acetate (CDB4124) on Progesterone Receptor Action in Breast Cancer Cells

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AU - Clare, Susan E.

AU - Lee, Oukseub

AU - Khan, Seema A.

AU - Kim, J. Julie

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