Dataset Information

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

ABSTRACT: Progesterone 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.Formalin-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.These findings suggest that the antiproliferative effects of aglepristone in canine mammary carcinomas are mediated by progesterone receptor isoform A.

SUBMITTER: Guil-Luna S

PROVIDER: S-EPMC4280049 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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

Guil-Luna Silvia S Stenvang Jan J Brünner Nils N De Andrés Francisco Javier FJ Rollón Eva E Domingo Víctor V Sánchez-Céspedes Raquel R Millán Yolanda Y Martín de Las Mulas Juana J

BMC veterinary research 20141217

<h4>Background</h4>Progesterone 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 th ...[more]

PMID: 25515784

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Project description:The incidence and prevalence of paraneoplastic glomerulopathy, especially associated with carcinoma, are a matter of debate and the causal link between cancer and glomerular diseases remains unclear. The aim of this study was to evaluate renal biopsies of selected bitches with spontaneous mammary gland carcinoma. We hypothesized that dogs with mammary carcinomas would show histologic evidence of glomerular pathology. A prospective study was performed in dogs with naturally occurring mammary carcinoma that were undergoing tumor resection and ovariohysterectomy. We evaluated renal biopsies of 32 bitches with spontaneous mammary gland carcinoma and 11 control dogs without mammary gland neoplasia. Samples were obtained from the left kidney and the biopsy material was divided for light microscopy (LM), immunofluorescence (IF) and transmission electron microscopy (TEM). Light microscopy abnormalities were identified in 78.1% of dogs with mammary carcinoma (n = 25) and in none of the dogs in the control group. Focal glomerular mesangial matrix expansion was the most common alteration (n = 15, 60.0%), but mesangial cell proliferation (n = 9, 36.0%) and focal segmental glomerulosclerosis (n = 9, 36.0%), synechiae (n = 7, 28.0%), and globally sclerotic glomeruli (n = 6, 24.0%) were also frequent in dogs with malignancy. Immunofluorescence microscopy revealed strong IgM staining was demonstrated in 64.3% (n = 18) of carcinoma dogs. Transmission electron microscopy from dogs with carcinoma revealed slight changes, the most frequent of which was faint sub-endothelial and mesangial deposits of electron-dense material (78%). Mesangial cell interpositioning and segmental effacement of podocyte foot processes were identified in some specimens (45%). Changes in the glomerulus and proteinuria are common in dogs with naturally occurring mammary carcinoma and this condition appears to provide an excellent large animal model for cancer-associated glomerulopathy in humans.

Project description:Expression of the progesterone receptor (PR) has been reported to influence survival outcomes in patients with ovarian high-grade serous carcinoma (HGSC). In the present study, we attempted to investigate the association among PR and its isoforms' expression, platinum sensitivity, and survival in ovarian HGSC. This retrospective study reviewed ovarian HGSC patients who received surgery followed by adjuvant chemotherapy. We analyzed total PR and PR isoform-B (PR-B) expression by immunohistochemical staining and quantified using the H-score. Then, we compared platinum sensitivity and survival outcomes between those patients with weak and strong PR-B expression. Cisplatin viability assays were carried out in ovarian HGSC cell lines (OC-3-VGH and OVCAR-3) with different PR-B expression. Among 90 patients, 49 and 41 patients were considered to have platinum-sensitive and platinum-resistant disease, respectively. Pearson's correlation model showed that the H-score of total PR correlated positively with PR-B (r = 0.813). The PR-B H-score of tumors was significantly higher in the platinum-sensitive group (p = 0.004). Multivariate analysis revealed that the PR-B H-score and optimal debulking status were independent factors predicting platinum sensitivity. When compared with strong PR-B expression, patients with weak PR-B had significantly poorer progression-free (p = 0.021) and cancer-specific survival (p = 0.046). In a cell model, cisplatin-resistant OC-3-VGH cells expressed a lower level of PR-B than wild-type cells. Overexpression of PR-B or progesterone could increase cisplatin sensitivity in both OC-3-VGH and OVCAR-3 cells via the mechanism of promoting cisplatin-related apoptosis. When compared to weak PR-B, ovarian HGSC patients with a strong PR-B expression had a better chance of platinum sensitivity and survival, and this finding was compatible with our experimental results. Progesterone seemed to be a platinum sensitizer, but the value of adding progesterone in the treatment of ovarian HGSC should be further investigated.

Dataset Information

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

Publications

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

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