Progesterone receptor-B enhances estrogen responsiveness of breast cancer cells via scaffolding PELP1-and estrogen receptor-containing transcription complexes

A. R. Daniel, A. L. Gaviglio, Todd P Knutson, Julie H Ostrander, A. B. D'Assoro, P. Ravindranathan, Y. Peng, G. V. Raj, Douglas Yee, Carol A Lange

Research output: Contribution to journalArticle

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Abstract

Progesterone and estrogen are important drivers of breast cancer proliferation. Herein, we probed estrogen receptor (ER) and progesterone receptor (PR) cross-talk in breast cancer models. Stable expression of PR-B in PR-low/ER+ MCF7 cells increased cellular sensitivity to estradiol and insulin-like growth factor 1 (IGF1), as measured in growth assays performed in the absence of exogenous progestin; similar results were obtained in PR-null/ER+ T47D cells stably expressing PR-B. Genome-wide microarray analyses revealed that unliganded PR-B induced robust expression of a subset of estradiol-responsive ER target genes, including cathepsin-D (CTSD). Estradiol-treated MCF7 cells stably expressing PR-B exhibited enhanced ER Ser167 phosphorylation and recruitment of ER, PR and the proline-, glutamate-and leucine-rich protein 1 (PELP1) to an estrogen response element in the CTSD distal promoter; this complex co-immunoprecipitated with IGF1 receptor (IGFR1) in whole-cell lysates. Importantly, ER/PR/PELP1 complexes were also detected in human breast cancer samples. Inhibition of IGF1R or phosphoinositide 3-kinase blocked PR-B-dependent CTSD mRNA upregulation in response to estradiol. Similarly, inhibition of IGF1R or PR significantly reduced ER recruitment to the CTSD promoter. Stable knockdown of endogenous PR or onapristone treatment of multiple unmodified breast cancer cell lines blocked estradiol-mediated CTSD induction, inhibited growth in soft agar and partially restored tamoxifen sensitivity of resistant cells. Further, combination treatment of breast cancer cells with both onapristone and IGF1R tyrosine kinase inhibitor AEW541 was more effective than either agent alone. In summary, unliganded PR-B enhanced proliferative responses to estradiol and IGF1 via scaffolding of ER-/PELP1/IGF1R-containing complexes. Our data provide a strong rationale for targeting PR in combination with ER and IGF1R in patients with luminal breast cancer.

Original languageEnglish (US)
Pages (from-to)506-515
Number of pages10
JournalOncogene
Volume34
Issue number4
DOIs
StatePublished - Jan 22 2015

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Proline
Leucine
Estrogen Receptors
Glutamic Acid
Progesterone Receptors
Estrogens
Breast Neoplasms
Cathepsin D
Estradiol
MCF-7 Cells
Somatomedins
Receptor Cross-Talk
progesterone receptor B
estrophilin
Somatomedin Receptors
Proteins
1-Phosphatidylinositol 4-Kinase
Response Elements
Progestins
Tamoxifen

Keywords

  • IGF1R
  • PELP1
  • breast cancer
  • cathepsin-D
  • estrogen receptor
  • progesterone receptor

Cite this

Progesterone receptor-B enhances estrogen responsiveness of breast cancer cells via scaffolding PELP1-and estrogen receptor-containing transcription complexes. / Daniel, A. R.; Gaviglio, A. L.; Knutson, Todd P; Ostrander, Julie H; D'Assoro, A. B.; Ravindranathan, P.; Peng, Y.; Raj, G. V.; Yee, Douglas; Lange, Carol A.

In: Oncogene, Vol. 34, No. 4, 22.01.2015, p. 506-515.

Research output: Contribution to journalArticle

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AU - Knutson, Todd P

AU - Ostrander, Julie H

AU - D'Assoro, A. B.

AU - Ravindranathan, P.

AU - Peng, Y.

AU - Raj, G. V.

AU - Yee, Douglas

AU - Lange, Carol A

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