Abstract P5-09-19: Progesterone receptor isoform A as a predictive marker of antiprogestin therapy in breast cancer: A tissue culture method to evaluate drug responsiveness
0
Citation
0
Reference
10
Related Paper
Abstract:
Abstract Two thirds of breast cancers express steroid hormone receptors and are susceptible to an endocrine therapy usually aimed to target the estrogen receptors (ER). There is however compelling evidence suggesting that progesterone receptors (PR) participate together with ER, modulating breast cancer growth. Based on our results obtained in an experimental breast cancer model in which antiprogestins induce complete regression of carcinomas with higher levels of PR isoform A (PR-A) than isoform B (PR-B), we propose that antiprogestins such as mifepristone (MFP) might be a possible therapeutic option for patients expressing high levels of PR-A. The goal of our study is to correlate the ratio of PR isoform expression, with the in vitro responsiveness of human breast cancer samples to MFP. Preliminary studies indicated that primary cultures of breast cancer samples overexpressing PR-A were responsive to MFP (10 nM) in vitro. However, since the rate of successful primary cultures was not encouraging (7%), we decided to develop a tissue culture assay to evaluate MFP responsiveness of breast cancer samples in vitro. Forty five breast cancer samples obtained from the General Pacheco´s Hospital, Buenos Aires, were kept in culture medium at room temperature and in dry ice. The former were cut in slices of 100 μm using a tissue chopper usually used to slice mouse nervous tissue for short incubations, and were incubated on filters in the presence of growth medium (fetal calf serum 10%) with or without MFP (10 nM), for 48 hs at 37º C. The slices were then fixed, paraffin embedded, and processed for Ki-67 staining to evaluate proliferating cells. Frozen samples were processed for Western blotting and the ratio of both PR isoforms was determined in nuclear extracts. In 17/45 (38%) of the samples valuable information was obtained. This was related with the quality (size and amount of viable cells) of the sample. The number of Ki-67 positive cells over the total viable cells was evaluated by a pathologist (M. May) in at least six different control or MFP-treated slices. From nine cases in which the Ki-67 index in control slices doubled the value obtained in MFP-treated slices (p<0.05), 8 were samples in which PR-A was higher than PR-B. MFP increased (p<0.05) the Ki-67 index in one sample with higher levels of PR-B than PR-A. No significant differences were observed in the remaining cases (null, equimolar or higher levels of PR-B than PR-A). We still plan to increase the number of samples in our study. Our data suggest that the tissue culture method developed is much more efficient than the primary cultures to evaluate drug or hormone responsiveness in breast cancer tissue. The results obtained herein support the proposal of PR-A as a predictive marker of antiprogestin therapy in breast cancer patients. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-09-19.Keywords:
Progesterone receptor
CA 15-3
Progesterone receptor
Cite
Citations (52)
Progesterone receptor
Cite
Citations (0)
<p>Morphological evaluation of CNBs and matched surgical samples; RNA-Seq analysis; Proteomics</p>
Progesterone receptor
Cite
Citations (0)
Progesterone receptor
Fallopian tube
Cite
Citations (23)
Progesterone receptor
Cite
Citations (0)
To provide the theoretical fundation for the further clinical application of mifepristone and anordrin compound. Materials Methods Ribonuclease protection assay was used for the detection and quantitation of estrogen and progesterone receptor mRNAs in human decidua from the termination of early pregnancy.Three groups, each of which had 6～8 cases, were studied. Results Compared to the normal control group, estrogen and progesterone receptor mRNAs increased significantly (P0.05) in the mifepristone group, whereas the changes in the group administrated mifepristone compound which contains anordrin were not obvious. Conclusions The result suggests that with the similar clinical effect, mifepristone compound has less side effect on the patients, thus being more suitable for the anti early pregnancy drug.
Decidua
Progesterone receptor
Early pregnancy factor
Cite
Citations (0)
OBJECTIVE: To investigate the regulatory effects of strogen,progesterone and mifepristone on the expression of two human progesterone receptor isoforms in endometrial carcinoma cells in vitro.METHODS: Three endometrial carcinoma cell lines were cultured in vitro: HECCA-A(PRA+),HECCA-B(PRB+) and HECCA-AB(PRA+,PRB+).The cells were incubated with estrogen,progesterone and mifepristone for 24 hours and 48 hours individually.The expressions of two progesterone receptor isoforms were detected by Western Blot.RESULTS: When stimulated by estrogen for 48 hours,the expression of PRA and the ratio of PRA/PRB in HECCA-A and HECCA-AB cells raised significantly(P0.05),while after being stimulated by progesterone or mifepristone,the expression of PRB in HECCA-B and HECCA-AB cells decreased,and the ratio of PRA/PRB raised significiantly(P0.05).CONCLUSION: Estrogen can up-regulate the expression of PRA at protein level,progesterone or mifepristone can decrease the protein expression of PRB.
Progesterone receptor
Cite
Citations (0)
Objective:To study the binding affinity(BA) to progesterone receptors and glucocorticoid receptors of the mifepristone.Method:With radioligand binding assay,the BA of mifepristone to the monkey uterus cytosol progesterone receptor and the rat liver glucocorticoid receptor was measured.Results:The BA of mifepristone and progesterone to progesterone receptor were 175.58%±19.20% and 100%,the 50% inhibitory concentration(IC_(50)) were(17.20±1.20)nmol/L and (30.20±2.31)nmol/L,P0.01.The BA of mifepristone and dexamethasone to glucocorticoid receptor were 344.41%±57.41% and 100%,the IC_(50) were (4.21±1.02)nmol/L and (14.50±1.89)nmol/L,P0.01.Conclusion:Mifepristone,as a strong agent of antiprogestin,can block progesterone and glucocorticoid activities.
Progesterone receptor
Antiglucocorticoid
Cite
Citations (0)
Progesterone receptor
Side chain
Antiglucocorticoid
Cite
Citations (23)