Progesterone receptor isoform A may regulate the effects of neoadjuvant aglepristone in canine mammary carcinoma

Abstract

BackgroundProgesterone receptors play a key role in the development of canine mammary tumours, and recent research has focussed on their possible value as therapeutic targets using antiprogestins. Cloning and sequencing of the progesterone receptor gene has shown that the receptor has two isoforms, A and B, transcribed from a single gene. Experimental studies in human breast cancer suggest that the differential expression of progesterone receptor isoforms has implications for hormone therapy responsiveness. This study examined the effects of the antiprogestin aglepristone on cell proliferation and mRNA expression of progesterone receptor isoforms A and B in mammary carcinomas in dogs treated with 20 mg/Kg of aglepristone (n = 22) or vehicle (n = 5) twice before surgery.ResultsFormalin-fixed, paraffin-embedded tissue samples taken before and after treatment were used to analyse total progesterone receptor and both isoforms by RT-qPCR and Ki67 antigen labelling. Both total progesterone receptor and isoform A mRNA expression levels decreased after treatment with aglepristone. Furthermore, a significant decrease in the proliferation index (percentage of Ki67-labelled cells) was observed in progesterone-receptor positive and isoform-A positive tumours in aglepristone-treated dogs.ConclusionsThese findings suggest that the antiproliferative effects of aglepristone in canine mammary carcinomas are mediated by progesterone receptor isoform A.Electronic supplementary materialThe online version of this article (doi:10.1186/s12917-014-0296-2) contains supplementary material, which is available to authorized users.

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

“…Interestingly, T47D-YA tumors expressing PR-A showed a slower growth rate than T47D-YB tumors expressing PR-B, and only the former were statistically significantly inhibited by tamoxifen (42) or MFP (18). These results are concordant with our current data and also with data obtained in preclinical murine, human, and canine models (17)(18)(19)43,44 This is the first study to perform ex vivo evaluations of the effect of antiprogestins in human breast cancers categorized according to the prevailing PR isoforms expressed. Initially, we adapted a tissue culture method used in the field of neurobiology (45); however, a similar method was recently reported for breast cancer samples (46).…”

Molecular studies on oestrogen α and progesterone receptors and histomorphometric analysis of canine uteri following aglepristone treatment

“…The current results clearly revealed that the progesterone antagonist, aglepristone, influenced downregulation of PR protein expression in the luminal epithelium, crypt and glandular epithelium. Nevertheless, in canine mammary cancer tissue, PR expression decreased after aglepristone treatment (Guil‐Luna et al., 2014). The standard deviations of PR were rather high in luminal epithelium, crypt and glandular because of highly variable H‐scores in the control samples and in some uterine layers.…”

Biological and clinical impact of imbalanced progesterone receptor isoform ratios in breast cancer

“…PR ligands may stimulate or inhibit breast cancer growth, and the challenge is to determine which patient will respond to either treatment. Breast cancers with PRA/PRB ratios may respond to antiprogestin treatments, as supported by preclinical assays (Wargon et al , 2015, clinical evidence in dogs (Guil-Luna et al 2014) and ex vivo data in human breast cancer tissue cultures (Rojas et al 2017).…”

“…In PR+ canine mammary carcinomas, higher levels of PRA than those of PRB were observed (Gracanin et al 2012, Guil-Luna et al 2014 In aglepristone-treated PRA+ tumors, both total PR and PRA mRNA expression levels decreased as well as the proliferation index, suggesting that PRA mediates the inhibitory effect.…”