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T47D xenografts treated with various combinations of ER- and PR-targeting therapies

ABSTRACT: Major roadblocks to developing effective progesterone receptor (PR)-targeted therapies in breast cancer include the lack of highly-specific PR modulators, a poor understanding of the pro- or anti-tumorigenic networks for PR isoforms and ligands, and an incomplete understanding of the cross talk between PR and estrogen receptor (ER) signaling. Through genomic analyses of xenografts treated with various clinically-relevant ER and PR-targeting drugs, we describe how the activation or inhibition of PR differentially reprograms estrogen signaling, resulting in the segregation of transcriptomes into separate PR agonist and antagonist-mediated groups. These findings address an ongoing controversy regarding the clinical utility of PR agonists and antagonists, alone or in combination with tamoxifen, for breast cancer management. Additionally, the two PR isoforms PRA and PRB, bind distinct genomic sites and interact with different sets of co-regulators to differentially modulate estrogen signaling to be either pro- or anti-tumorigenic. Of the two isoforms, PRA inhibited gene expression and ER chromatin binding significantly more than PRB. Differential gene expression was observed in PRA and PRB-rich patient tumors and importantly, PRA-rich gene signatures had poorer survival outcomes. In support of antiprogestin responsiveness of PRA-rich tumors, gene signatures associated with PR antagonists, but not PR agonists, predicted better survival outcomes. This better patient survival associated with PR antagonists versus PR agonists treatments was further reflected in the higher anti-tumor activity of combination therapies of tamoxifen with PR antagonists and modulators. The study suggests that distinguishing common effects observed due to concomitant interaction of another receptor with its ligand (agonist or antagonist) from unique isoform and ligand-specific effects will guide the development of biomarkers for patient selection and translation of PR-targeted therapies to the clinic.

ORGANISM(S): Homo sapiens

PROVIDER: GSE80619 | GEO | 2017/12/31

SECONDARY ACCESSION(S): PRJNA319523

REPOSITORIES: GEO

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Project description:Major roadblocks to developing effective progesterone receptor (PR)-targeted therapies in breast cancer include the lack of highly-specific PR modulators, a poor understanding of the pro- or anti-tumorigenic networks for PR isoforms and ligands, and an incomplete understanding of the cross talk between PR and estrogen receptor (ER) signaling. Through genomic analyses of xenografts treated with various clinically-relevant ER and PR-targeting drugs, we describe how the activation or inhibition of PR dictates distinct ER and PR chromatin binding and differentially reprograms estrogen signaling, resulting in the segregation of transcriptomes into separate PR agonist and antagonist-mediated groups. These findings address an ongoing controversy regarding the clinical utility of PR agonists and antagonists, alone or in combination with tamoxifen, for breast cancer management. Genomic analyses of the two PR isoforms, PRA and PRB, indicate that these isoforms bind distinct genomic sites and interact with different sets of co-regulators to differentially modulate gene expression as well as pro- or anti-tumorigenic phenotypes. Of the two isoforms, PRA inhibited gene expression and ER chromatin binding significantly more than PRB. Of note, the two isoforms reprogrammed estrogen activity to be either pro or anti-tumorigenic. In concordance to the in-vitro observations, differential gene expression was observed in PRA and PRB-rich patient tumors and importantly, PRA-rich gene signatures had poorer survival outcomes. In support of antiprogestin responsiveness of PRA-rich tumors, gene signatures associated with PR antagonists, but not PR agonists, predicted better survival outcomes. This differential of better patient survival associated with PR antagonists versus PR agonists treatments was further reflected in the higher anti-tumor activity of combination therapies of tamoxifen with PR antagonists and modulators. Knowledge of various determinants of PR action and their interactions with estrogen signaling to differentially modulate breast cancer biology should serve as a guide to the development of biomarkers for patient selection and translation of PR-targeted therapies to the clinic.

Project description:The progesterone receptor isoforms PRA and PRB are implicated in breast cancer development and metastasis. Expression ratio PRA/PRB is imbalanced in such cancers under the influence of MAPK-dependent extracellular stimuli that strongly impact progesterone-responsiveM- transcriptional regulation. In order to determine the isoform-specific regulated genes M- in a metastatic cancer cell, we established the iPRAB cell line derived from MDA-MB-231 mammary cancer cells (ER-, PR-). This cell lineM- conditionally expressed PRA and/or PRB under the control of RSL1 and doxycycline (Dox) non-steroid ligands, respectively, in a dose-dependent manner. The bi-inducible expression system was generated using a combination of the Rheoswitch (NE Biolabs) and T-Rex (Invitrogen) vector systems as described in the article. We investigated the transcriptomes obtained in cells treated by either RSL1 (for PRA), or Dox (for PRB), or RSL1 + Dox (for PRA + PRB) for 24 h and then by either 10 nM progesterone (+) or vehicle (-) for 6 h. Control experiments were obtained from cells grown in the absence of RSL1, doxycycline and in the presence of progesterone (O+) or vehicle (O-). Experimental conditions of PRA/PRB expression ratio were ranged from 0.1 to 10, and the maximum expression of a given isoform was set to 300 fmol per mg proteins following 24 h induction. After removing redundant probes and pseudogens, the processed data identified 1014 distinct regulated genes subdivised in 3 classes : genes responding either only to unliganded PR isoforms (-), or only to liganded (+) or to both conditions (mixed M-1). Each classe was subdivided according to isoform specificity criteria (A, B, AB, A&B, A&AB, B&AB, A&B&AB) leading to define 3X7 clusters of genes per classe. Each subset was then further analyzed by complete hierarchical clustering through up or down-regulation criteria. These data indicated that PR target genes selectivity is highly dependent of PRA/PRB expression ratio as well as ligand status and highlight the major impact of PR on transcriptional regulation of genes involved in breast cancer and metastasis.

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T47D xenografts treated with various combinations of ER- and PR-targeting therapies

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