Progesterone Receptor Isoform Ratio: A Breast Cancer Prognostic and Predictive Factor for Antiprogestin Responsiveness

Rojas, Paulina S.; May, María; Sequeira, Gonzalo R.; Elía, Andrés; Alvarez, Michelle; Martínez, Paula; González, Pedro Horacio; Hewitt, Stephen M.; He, Xiaping; Perou, Charles M.; Molinolo, Alfredo A.; Gibbons, Luz; Abba, Martı́n C.; Rojas, Paola; Lanari, Claudia

doi:10.1093/jnci/djw317

Cited by 52 publications

(72 citation statements)

References 54 publications

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“…The staining was not homogeneous suggesting that the inducer is not equally distributed in the tumour. Figure 2A,B, and a PR negative breast cancer core, the three in the same TMA [3], is shown to reinforce the results shown in Figure 2A,B. The stained nuclei have been quantified as described in B.…”

Section: Resultssupporting

confidence: 75%

“…The average number of positive nuclei with respect to total tumour cells in 10 different representative fields of T1 and T2 is shown in the adjacent bar charts (± SD). (C) IHC of T47D‐YA and ‐YB xenograft cores from a different experiment than those shown in Figure 2A,B, and a PR negative breast cancer core, the three in the same TMA , is shown to reinforce the results shown in Figure 2A,B. The stained nuclei have been quantified as described in B.…”

Section: Resultsmentioning

confidence: 53%

“…We have recently suggested that only those patients with breast cancers expressing levels of PRA higher than those of PRB are amenable to antiprogestin treatment. Determination of the PRA/PRB ratio, as mentioned previously, may have an intrinsic prognostic and predictive value for breast cancer treatment . Thus, the use of validated tools to measure this ratio is mandatory.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Resultssupporting

confidence: 75%

Section: Resultsmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 99%

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Isoform specificity of progesterone receptor antibodies

Fabris

Abascal

Giulianelli

et al. 2017

The Journal of Pathology CR

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“…PRBΔ4 mRNA expression has already been detected in breast cancer tissues. 35,36 Using selected human breast tumor samples from our tumor bank, 37 we show that the samples in which the intermediate band between PRB and PRA coincides with the PRBΔ4 band of T47D-Y PRBΔ4 transfected cells (Fig. 6a, right), also expressed PRBΔ4 mRNA (Fig.…”

Section: Prbδ4 Expression In Human Breast Cancermentioning

confidence: 89%

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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“…The increasing understanding of PR-A and PR-B as distinct, and even contradictory, growth regulators has encouraged the exploration of the role of the relative expression of PR-A and PR-B in cancer types such as EC 28 and breast cancer. 29,30 Jongen et al found shorter diseasefree survival and shorter overall survival for women with EC with a ratio of PR-A:PR-B < 1. The results of the present study demonstrated an 11-fold increased odds for relapse in women with pre-treatment PR-A:PR-B ≤ 1 compared with women with PR-A:PR-B > 1.…”

Section: Discussionmentioning

confidence: 99%

Significance of progesterone receptors (PR‐A and PR‐B) expression as predictors for relapse after successful therapy of endometrial hyperplasia: a retrospective cohort study

Sletten

Arnes

Lyså

et al. 2019

BJOG

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Objective After successful progestin therapy for endometrial hyperplasia (EH), the risk of relapse remains. We aimed to assess if immunohistochemical (IHC) expression of progesterone receptor isoforms, PR‐A and PR‐B, in endometrial glands and stroma in pre‐treatment endometrial biopsies was related to relapse of EH. Design and setting Biopsy material originated from women with low‐risk and medium‐risk EH recruited to a recent Norwegian multicentre randomised trial. Participants (n = 153) had been treated for 6 months with three different progestin regimens. Population One hundred and thirty‐five of the 153 women achieved therapy response and underwent follow up for 24 months after therapy withdrawal. Fifty‐five women relapsed during follow up. Pre‐treatment endometrial biopsies from 94 of the 135 responding women were available for IHC staining. Methods Immunohistochemical staining was performed separately for PR‐A and PR‐B and IHC expression was evaluated in endometrial glands and stroma by a histological score (H‐score) using light microscopy. Main outcome measure Immunohistochemical expression of PR‐A and PR‐B in endometrial glands and stroma in women with or without relapse of EH. Results Low PR‐A in endometrial glands (P = 0.013) and stroma (P < 0.001), and high PR‐B in endometrial glands (P = 0.001) in pre‐treatment endometrial biopsy have a statistically significant association with relapse of EH. Women with a pre‐treatment ratio of PR‐A:PR‐B ≤ 1 have a higher risk of relapse (71%) compared with women with a ratio of PR‐A:PR‐B > 1 (19%; P < 0.001). Conclusion Immunohistochemical expression of PR‐A and PR‐B in pre‐treatment endometrial biopsy proves valuable as a predictor of relapse in EH. Tweetable abstract Pre‐treatment endometrial expression of PR‐A and PR‐B is a valuable predictor of relapse in endometrial hyperplasia.

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Progesterone Receptor Isoform Ratio: A Breast Cancer Prognostic and Predictive Factor for Antiprogestin Responsiveness

Abstract: The PRA/PRB ratio is a prognostic and predictive factor for antiprogestin responsiveness in breast cancer.

Cited by 52 publications

References 54 publications

Isoform specificity of progesterone receptor antibodies

Isoform specificity of progesterone receptor antibodies

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

Significance of progesterone receptors (PR‐A and PR‐B) expression as predictors for relapse after successful therapy of endometrial hyperplasia: a retrospective cohort study

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