Progestin and antiprogestin responsiveness in breast cancer is driven by the <scp>PRA</scp>/<scp>PRB</scp> ratio via<scp>AIB</scp>1 or <scp>SMRT</scp> recruitment to the <scp>CCND</scp>1 and <scp>MYC</scp> promoters

Wargon, Victoria; Riggio, Marina; Giulianelli, Sebastián; Sequeira, Gonzalo R.; Rojas, Paola; May, María; Polo, María L.; Gorostiaga, María A.; Jacobsen, Britta M.; Molinolo, Alfredo A.; Novaro, Virginia; Lanari, Claudia

doi:10.1002/ijc.29304

Cited by 37 publications

(56 citation statements)

References 56 publications

(104 reference statements)

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“…The effect of MFP is less clear. As shown in previous studies, MFP activates PR, which binds to gene promoters . Nevertheless, gene transcription is blocked due to recruitment of corepressors that turn off gene transcription .…”

Section: Discussionsupporting

confidence: 65%

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FGF2 induces breast cancer growth through ligand‐independent activation and recruitment of ERα and PRBΔ4 isoform to MYC regulatory sequences

Giulianelli

Riggio

Guillardoy

et al. 2019

Intl Journal of Cancer

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Progression to hormone‐independent growth leading to endocrine therapy resistance occurs in a high proportion of patients with estrogen receptor alpha (ERα) and progesterone receptors (PR) positive breast cancer. We and others have previously shown that estrogen‐ and progestin‐induced tumor growth requires ERα and PR interaction at their target genes. Here, we show that fibroblast growth factor 2 (FGF2)‐induces cell proliferation and tumor growth through hormone‐independent ERα and PR activation and their interaction at the MYC enhancer and proximal promoter. MYC inhibitors, antiestrogens or antiprogestins reverted FGF2‐induced effects. LC–MS/MS identified 700 canonical proteins recruited to MYC regulatory sequences after FGF2 stimulation, 397 of which required active ERα (ERα‐dependent). We identified ERα‐dependent proteins regulating transcription that, after FGF2 treatment, were recruited to the enhancer as well as proteins involved in transcription initiation that were recruited to the proximal promoter. Also, among the ERα‐dependent and independent proteins detected at both sites, PR isoforms A and B as well as the novel protein product PRBΔ4 were found. PRBΔ4 lacks the hormone‐binding domain and was able to induce reporter gene expression from estrogen‐regulated elements and to increase cell proliferation when cells were stimulated with FGF2 but not by progestins. Analysis of the Cancer Genome Atlas data set revealed that PRBΔ4 expression is associated with worse overall survival in luminal breast cancer patients. This discovery provides a new mechanism by which growth factor signaling can engage nonclassical hormone receptor isoforms such as PRBΔ4, which interacts with growth‐factor activated ERα and PR to stimulate MYC gene expression and hence progression to endocrine resistance.

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Section: Discussionsupporting

confidence: 65%

“…As shown in previous studies, MFP activates PR, which binds to gene promoters. 54,55 Nevertheless, gene transcription is blocked due to recruitment of corepressors that turn off gene transcription. 56 In our experiments, MFP maintained ERα and PR binding at the enhancer region.…”

Section: Discussionmentioning

confidence: 99%

FGF2 induces breast cancer growth through ligand‐independent activation and recruitment of ERα and PRBΔ4 isoform to MYC regulatory sequences

Giulianelli

Riggio

Guillardoy

et al. 2019

Intl Journal of Cancer

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“…To further rule out that the faint band visible at the PRA molecular weight in the T47D-YB WB could account for the positive staining, we immunostained, using clone 16 and IHC, a TMA composed of breast cancer samples with different PRA/PRB ratios that included cores of T47D-YA and -YB xenografts as controls. The exclusive expression of PRA or PRB of these control xenografts included in the TMA has been shown by WB in a previous study [8]. Intense nuclear staining was observed in both cases and no differences between T47D-YA or -YB xenografts were observed using clone 16 ( Figure 2C).…”

Section: Resultssupporting

confidence: 79%

Isoform specificity of progesterone receptor antibodies

Fabris

Abascal

Giulianelli

et al. 2017

The Journal of Pathology CR

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Progesterone receptors (PR) are prognostic and predictive biomarkers in hormone‐dependent cancers. Two main PR isoforms have been described, PRB and PRA, that differ only in that PRB has 164 extra N‐terminal amino acids. It has been reported that several antibodies empirically exclusively recognize PRA in formalin‐fixed paraffin‐embedded (FFPE) tissues. To confirm these findings, we used human breast cancer xenograft models, T47D‐YA and ‐YB cells expressing PRA or PRB, respectively, MDA‐MB‐231 cells modified to synthesize PRB, and MDA‐MB‐231/iPRAB cells which can bi‐inducibly express either PRA or PRB. Cells were injected into immunocompromised mice to generate tumours exclusively expressing PRA or PRB. PR isoform expression was verified using immunoblots. FFPE samples from the same tumours were studied by immunohistochemistry using H‐190, clone 636, clone 16, and Ab‐6 anti‐PR antibodies, the latter exclusively recognizing PRB. Except for Ab‐6, all antibodies displayed a similar staining pattern. Our results indicate that clones 16, 636, and the H‐190 antibody recognize both PR isoforms. They point to the need for more stringency in evaluating the true specificity of purported PRA‐specific antibodies as the PRA/PRB ratio may have prognostic and predictive value in breast cancer.

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“…Elevated levels of NCOA3/AIB1 enhance ERα actions in breast cancer through a variety of actions and are associated with worse disease free survival. This has been primarily examined within the context of ERα signaling but is also associated with the actions of other Type 1 receptors including PR, AR and GR(81–86). Similarly, the genome-wide binding of the transcriptional co-repressors NCOR1 and NCOR2/SMRT maintains distal enhancer regions in an epigenetically repressed, yet poised, state until released(87, 88).…”

Section: Introductionmentioning

confidence: 99%

Pan-Cancer Analyses of the Nuclear Receptor Superfamily

Long

Campbell

2015

Nuclear Receptor Research

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Nuclear receptors (NR) act as an integrated conduit for environmental and hormonal signals to govern genomic responses, which relate to cell fate decisions. We review how their integrated actions with each other, shared co-factors and other transcription factors are disrupted in cancer. Steroid hormone nuclear receptors are oncogenic drivers in breast and prostate cancer and blockade of signaling is a major therapeutic goal. By contrast to blockade of receptors, in other cancers enhanced receptor function is attractive, as illustrated initially with targeting of retinoic acid receptors in leukemia. In the post-genomic era large consortia, such as The Cancer Genome Atlas, have developed a remarkable volume of genomic data with which to examine multiple aspects of nuclear receptor status in a pan-cancer manner. Therefore to extend the review of NR function we have also undertaken bioinformatics analyses of NR expression in over 3000 tumors, spread across six different tumor types (bladder, breast, colon, head and neck, liver and prostate). Specifically, to ask how the NR expression was distorted (altered expression, mutation and CNV) we have applied bootstrapping approaches to simulate data for comparison, and also compared these NR findings to 12 other transcription factor families. Nuclear receptors were uniquely and uniformly downregulated across all six tumor types, more than predicted by chance. These approaches also revealed that each tumor type had a specific NR expression profile but these were most similar between breast and prostate cancer. Some NRs were down-regulated in at least five tumor types (e.g. NR3C2/MR and NR5A2/LRH-1)) whereas others were uniquely down-regulated in one tumor (e.g. NR1B3/RARG). The downregulation was not driven by copy number variation or mutation and epigenetic mechanisms maybe responsible for the altered nuclear receptor expression.

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Progestin and antiprogestin responsiveness in breast cancer is driven by the PRA/PRB ratio viaAIB1 or SMRT recruitment to the CCND1 and MYC promoters

Cited by 37 publications

References 56 publications

FGF2 induces breast cancer growth through ligand‐independent activation and recruitment of ERα and PRBΔ4 isoform to MYC regulatory sequences

FGF2 induces breast cancer growth through ligand‐independent activation and recruitment of ERα and PRBΔ4 isoform to MYC regulatory sequences

Isoform specificity of progesterone receptor antibodies

Pan-Cancer Analyses of the Nuclear Receptor Superfamily

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