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Claudia Lanari - One of the best experts on this subject based on the ideXlab platform.
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Progesterone receptor isoform ratio dictates Antiprogestins/progestins effects on metastatic breast cancer models
Annals of Oncology, 2019Co-Authors: María Florencia Abascal, Sebastián Giulianelli, Marc Lombes, M. Alvarez, G. Sequeira, S. Vanzulli, Andres Elia, Gabriela Pataccini, Claudia LanariAbstract:Abstract Background The use of progesterone receptor (PR) ligands for adjuvant breast cancer treatment remains controversial. We propose that Antiprogestins inhibit the breast tumor growth with high isoform A (PRA)/isoform B (PRB) ratio while progestins may inhibit those with opposite ratios. Methods We used metastatic models with different PR isoform ratios to evaluate the effect of Antiprogestins [mifepristone (MFP), aglepristone (AGLE), telapristone acetate (TLP), ulipristal acetate (UPA), or progestins [medroxyprogesterone acetate (MPA) or progesterone (Pg)]. Murine BALB/c tumors with PRA>PRB (C7-2-HI) and PRB>PRA (C7-HI), human MDA-MB-231 cells transfected with PRB and the inducible MDA-MB-231-iPRAB cells were inoculated into NSG mice. Results All Antiprogestins inhibited C7-2-HI tumor growth rate (MFP 88%, TLP 59% UPA 70%) and the onset of lymph node and lung metastasis. AGLE induced complete tumor regression. The progestin MPA, increased tumor size and metastasis in a 60% (p PRA), AGLE, UPA or MFP increased tumor growth and/or metastasis (p Conclusions Progestins/Antiprogestins stimulate or inhibit, respectively tumor growth/metastasis of mammary carcinomas with high PRA/PRB ratio, and they may exert opposite effects in tumors with low PRA/PRB ratio. These findings highlight the relevance of evaluating PR isofor.m ratio prior to PR ligand treatment on human breast cancer. Legal entity responsible for the study CONICET. Funding CONICET; INC, ANPCYT. Disclosure All authors have declared no conflicts of interest.
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Abstract A43: Increased cyclin A expression is associated with Antiprogestin resistance and progesterone receptor isoforms ratio in experimental models of breast cancer
Resistance Mechanisms, 2018Co-Authors: Marina Ayre, Claudia Lanari, Britta M Jacobsen, Melina Elena Bilinski, Victoria T. FabrisAbstract:Deregulation of cyclin A expression has been associated with prognosis and tamoxifen responsiveness in breast cancer. We have previously reported an overexpression of cyclin A in two Antiprogestin-resistant tumors derived from a hormone-dependent mammary carcinoma induced by medroxyprogesterone acetate (MPA). MPA-induced tumors show high levels of estrogen (ER) and progesterone receptors (PR) and transit through different stages of hormone dependency. Taking into account that Antiprogestin-sensitive tumors show higher levels of PR isoform A (PRA) than isoform B (PRB), and that the opposite ratio is observed in the Antiprogestin-resistant tumors, we decided to examine the expression of cyclin A in other experimental models containing different PRA/PRB ratios. An increase in cyclin A expression was observed by Western blot (WB) in the acquired Antiprogestin-resistant variant C7-2-HIR and in the constitutive resistant C7-HI tumor (1.7 fold and 1.5 fold, respectively) compared to the Antiprogestin-responsive tumor C7-2-HI (p Citation Format: Marina Ayre, Melina E. Bilinski, Britta M. Jacobsen, Claudia Lanari, Victoria T. Fabris. Increased cyclin A expression is associated with Antiprogestin resistance and progesterone receptor isoforms ratio in experimental models of breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A43.
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abstract 1399 Antiprogestin responsiveness of a human breast cancer xenograft model overexpressing progesterone receptors isoforms a pra or b prb
Cancer Research, 2013Co-Authors: Gonzalo Ricardo Sequeira, Paola Rojas, Maria May, Claudia LanariAbstract:Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Endocrine therapies in breast cancer are designed to target directly or indirectly the estrogen receptors alpha (ERα). There is increasing evidence indicating that progesterone receptors (PR) are involved as ERα modulating breast cancer growth. Antiprogestins had been used in clinical trials in patients who have failed to other therapies; however, the results were not very clear. Our laboratory has developed an experimental murine model of breast cancer in which mammary carcinomas, expressing ER and PR, transit through different stages of hormone dependency. We demonstrated using this model, that only tumors with higher levels of PRA than PRB were those responsive to Antiprogestin treatment. Moreover, the Antiprogestin mifepristone (MFP) was able to stimulate the growth of tumors overexpressing PRB. The aim of this study was to move into a human in mouse scenario in order to test our hypothesis postulating that only breast cancer patients with higher levels of PRA than PRB are susceptible to MFP treatment. T47D-YA and T47D-YB kindly provided by Dr. K. Horwitz (University of Colorado, Denver), were inoculated sc with matrigel into the right and left flanks respectively of female NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice (5/group; 3 experiments) that have been implanted one week before with a sc 17-β-estradiol pellet (0.5mg). After 10 days, when tumors reached a size greater than 20 mm2, the mice were treated with silastic or MFP (6 mg) pellets sc. In other experiments MFP was administered as daily injections of 10 mg/kg/body weight. Animals were followed for 2 weeks. A significant decrease in tumor size was only registered in T47D-YA tumors treated with MFP (p<0.05). Interestingly the T47D-YB tumors growing in the contralateral flank of the same mice increased their size with MFP treatment. They reached a size even larger than control -YB tumors (p<0.05). T47D-YA tumors showed nuclear MYC and Cyclin D1 staining whereas a cytoplasmic staining was observed in MFP-treated tumors 72 hours after treatment (immunohistochemistry). Conversely, an intense nuclear staining of both proteins was observed in T47D-YB tumors growing with MFP treatment. It can be concluded that in this human in mouse model, a specific inhibitory effect of MFP is only obtained in xenografts expressing PRA, while a stimulatory effect may be achieved in tumors expressing only PRB. These results are in agreement with our data in murine tumors and as a whole suggest that Antiprogestins may be excellent therapeutic tools for breast cancer patients with higher levels of PRA than PRB. Citation Format: Gonzalo R. Sequeira, Paola Rojas, Maria May, Claudia Lanari. Antiprogestin responsiveness of a human breast cancer xenograft model overexpressing progesterone receptors isoforms A (PRA) or B (PRB). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1399. doi:10.1158/1538-7445.AM2013-1399
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Antiprogestins in breast cancer treatment: are we ready?
Endocrine-related cancer, 2012Co-Authors: Claudia Lanari, Victoria Wargon, Paola Rojas, Alfredo MolinoloAbstract:Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death in females worldwide. It is accepted that breast cancer is not a single disease, but instead constitutes a spectrum of tumor subtypes with distinct cellular origins, somatic changes, and etiologies. Molecular gene expression studies have divided breast cancer into several categories, i.e. basal-like, ErbB2 enriched, normal breast-like (adipose tissue gene signature), luminal subtype A, luminal subtype B, and claudin-low. Chances are that as our knowledge increases, each of these types will also be subclassified. More than 66% of breast carcinomas express estrogen receptor alpha (ERα) and respond to antiestrogen therapies. Most of these ER+ tumors also express progesterone receptors (PRs), the expression of which has been considered as a reliable marker of a functional ER. In this paper we will review the evidence suggesting that PRs are valid targets for breast cancer therapy. Experimental data suggest that both PR isoforms (A and B) have different roles in breast cancer cell growth, and Antiprogestins have already been clinically used in patients who have failed to other therapies. We hypothesize that Antiprogestin therapy may be suitable for patients with high levels of PR-A. This paper will go over the experimental evidence of our laboratory and others supporting the use of Antiprogestins in selected breast cancer patients.
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Abstract 1315: DNMT and HDAC inhibitors resensitize resistant tumors to Antiprogestin therapy in a mouse breast cancer model
Carcinogenesis, 2011Co-Authors: Victoria Wargon, Claudia LanariAbstract:Mouse mammary carcinomas induced by medroxyprogesterone acetate (MPA) are maintained by syngeneic transplantation and tumor variants with different hormone responsiveness have been generated. Tumors which grow without the MPA supply were defined as hormone independent (HI). Most of these tumors regress after Antiprogestin (mifepristone, MIF) administration, while others show constitutive resistance to hormone therapy. We have previously demonstrated that responsive tumors show higher levels of progesterone receptor A (PRA) than PRB, while the opposite occurs in resistant tumors, indicating that the PR isoform ratio might be a predictor of Antiprogestin responsiveness. We have also demonstrated that in constitutive resistant tumors PRA is silenced by methylation of its promoter, and that treatment with 5azadC (demethylating agent) induces PRA expression and tumors partially recover Antiprogestin responsiveness. The aim of this study was to investigate whether the co-treatment with DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors would enhance even more the responsiveness to MIF. For this purpose we investigated the expression of HDAC1 in constitutive resistant tumors and whether treatment of these tumors with 5azadC and trichostatin A (TSA; HDAC inhibitor) restored MIF responsiveness better than 5azadC alone. The constitutive resistant tumor 59-HI showed a higher expression of HDAC1 as compared to the Antiprogestin sensititive tumor 59-2-HI as determined by Western blot (p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1315. doi:10.1158/1538-7445.AM2011-1315
Victoria Wargon - One of the best experts on this subject based on the ideXlab platform.
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progestin and Antiprogestin responsiveness in breast cancer is driven by the pra prb ratio via aib1 or smrt recruitment to the ccnd1 and myc promoters
International Journal of Cancer, 2015Co-Authors: Victoria Wargon, Sebastián Giulianelli, Marina Riggio, Gonzalo Ricardo Sequeira, Paola Alejandra Rojas, Maria May, Maria Laura Polo, Maria Alicia Gorostiaga, Britta M Jacobsen, Alfredo A MolinoloAbstract:There is emerging interest in understanding the role of progesterone receptors (PRs) in breast cancer. The aim of this study was to investigate the proliferative effect of progestins and Antiprogestins depending on the relative expression of the A (PRA) and B (PRB) isoforms of PR. In mifepristone (MFP)-resistant murine carcinomas Antiprogestin responsiveness was restored by re-expressing PRA using demethylating agents and histone deacetylase inhibitors. Consistently, in two human breast cancer xenograft models, one manipulated to overexpress PRA or PRB (IBH-6 cells), and the other expressing only PRA (T47D-YA) or PRB (T47D-YB), MFP selectively inhibited the growth of PRA-overexpressing tumors and stimulated IBH-6-PRB xenograft growth. Furthermore, in cells with high or equimolar PRA/PRB ratios, which are stimulated to proliferate in vitro by progestins, and are inhibited by MFP, MPA increased the interaction between PR and the coactivator AIB1, and MFP favored the interaction between PR and the corepressor SMRT. In a PRB-dominant context in which MFP stimulates and MPA inhibits cell proliferation, the opposite interactions were observed. Chromatin immunoprecipitation assays in T47D cells in the presence of MPA or MFP confirmed the interactions between PR and the coregulators at the CCND1 and MYC promoters. SMRT downregulation by siRNA abolished the inhibitory effect of MFP on MYC expression and cell proliferation. Our results indicate that Antiprogestins are therapeutic tools that selectively inhibit PRA-overexpressing tumors by increasing the SMRT/AIB1 balance at the CCND1 and MYC promoters.
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Antiprogestins in breast cancer treatment: are we ready?
Endocrine-related cancer, 2012Co-Authors: Claudia Lanari, Victoria Wargon, Paola Rojas, Alfredo MolinoloAbstract:Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death in females worldwide. It is accepted that breast cancer is not a single disease, but instead constitutes a spectrum of tumor subtypes with distinct cellular origins, somatic changes, and etiologies. Molecular gene expression studies have divided breast cancer into several categories, i.e. basal-like, ErbB2 enriched, normal breast-like (adipose tissue gene signature), luminal subtype A, luminal subtype B, and claudin-low. Chances are that as our knowledge increases, each of these types will also be subclassified. More than 66% of breast carcinomas express estrogen receptor alpha (ERα) and respond to antiestrogen therapies. Most of these ER+ tumors also express progesterone receptors (PRs), the expression of which has been considered as a reliable marker of a functional ER. In this paper we will review the evidence suggesting that PRs are valid targets for breast cancer therapy. Experimental data suggest that both PR isoforms (A and B) have different roles in breast cancer cell growth, and Antiprogestins have already been clinically used in patients who have failed to other therapies. We hypothesize that Antiprogestin therapy may be suitable for patients with high levels of PR-A. This paper will go over the experimental evidence of our laboratory and others supporting the use of Antiprogestins in selected breast cancer patients.
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Abstract 1315: DNMT and HDAC inhibitors resensitize resistant tumors to Antiprogestin therapy in a mouse breast cancer model
Carcinogenesis, 2011Co-Authors: Victoria Wargon, Claudia LanariAbstract:Mouse mammary carcinomas induced by medroxyprogesterone acetate (MPA) are maintained by syngeneic transplantation and tumor variants with different hormone responsiveness have been generated. Tumors which grow without the MPA supply were defined as hormone independent (HI). Most of these tumors regress after Antiprogestin (mifepristone, MIF) administration, while others show constitutive resistance to hormone therapy. We have previously demonstrated that responsive tumors show higher levels of progesterone receptor A (PRA) than PRB, while the opposite occurs in resistant tumors, indicating that the PR isoform ratio might be a predictor of Antiprogestin responsiveness. We have also demonstrated that in constitutive resistant tumors PRA is silenced by methylation of its promoter, and that treatment with 5azadC (demethylating agent) induces PRA expression and tumors partially recover Antiprogestin responsiveness. The aim of this study was to investigate whether the co-treatment with DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors would enhance even more the responsiveness to MIF. For this purpose we investigated the expression of HDAC1 in constitutive resistant tumors and whether treatment of these tumors with 5azadC and trichostatin A (TSA; HDAC inhibitor) restored MIF responsiveness better than 5azadC alone. The constitutive resistant tumor 59-HI showed a higher expression of HDAC1 as compared to the Antiprogestin sensititive tumor 59-2-HI as determined by Western blot (p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1315. doi:10.1158/1538-7445.AM2011-1315
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Hypermethylation of the progesterone receptor A in constitutive Antiprogestin-resistant mouse mammary carcinomas
Breast Cancer Research and Treatment, 2011Co-Authors: Victoria Wargon, Sandra V. Fernandez, Mercedes Goin, Sebastián Giulianelli, Jose Russo, Claudia LanariAbstract:Most breast carcinomas that are estrogen receptor (ER) and progesterone receptor (PR) positive respond initially to an endocrine therapy, but over time, they develop resistance (acquired hormone resistance). Others, however, fail to respond from the beginning (constitutive resistance). Overcoming hormone resistance is one of the major desirable aims in breast cancer treatment. Using the medroxyprogesterone acetate (MPA)-induced breast cancer mouse model, we have previously demonstrated that Antiprogestin-responsive tumors show a higher expression level of PR isoform A (PRA) than PR isoform B (PRB), while tumors with constitutive or acquired resistance show a higher expression level of PRB. The aim of this study was to investigate whether PRA silencing in resistant tumors was due to PRA methylation. The CpG islands located in the PRA promoter and the first exon were studied by methylation-specific PCR (MSP) in six different tumors: two Antiprogestin-responsive, two constitutive-resistant, and two with acquired resistance. Only in constitutive-resistant tumors, PRA expression was silenced by DNA methylation. Next, we evaluated the effect of a demethylating agent, 5-aza-2′-deoxycytidine, on PRA expression and Antiprogestin responsiveness. In constitutive-resistant tumors, 5-aza-2′ - deoxycytidine treatment in vitro and in vivo restored PRA expression and Antiprogestin RU-486 responsiveness. Furthermore, high levels of DNA methyltransferase (Dnmts) 1 and 3b were detected in these tumors. In conclusion, our results suggest that methyltransferase inhibitors in combination with Antiprogestins may be effective in the treatment of constitutive-resistant carcinomas with a high DNA methyltransferase level.
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reversal of Antiprogestin resistance and progesterone receptor isoform ratio in acquired resistant mammary carcinomas
Breast Cancer Research and Treatment, 2009Co-Authors: Victoria Wargon, Paola Rojas, Alfredo A Molinolo, Luisa A Helguero, Julieta Bolado, Virginia Novaro, Claudia LanariAbstract:To explore mechanisms related to hormone resistance, three resistant variants of the MPA mouse breast cancer tumor model with low levels of progesterone receptor (PR) isoform A (PR-A)/high PR-B expression were developed by prolonged selective pressure with Antiprogestins. The resistant phenotype of one tumor line was reversed spontaneously after several consecutive passages in syngeneic BALB/c mice or by 17-β-estradiol or tamoxifen treatment, and this reversion was significantly associated with an increase in PR-A expression. The responsive parental tumors disclosed low activation of ERK and high activation of AKT; resistant tumors on the other hand, showed the opposite, and this was associated with a higher metastatic potential, that did not revert. This study shows for the first time in vivo a relationship between PR isoform expression and Antiprogestin responsiveness, demonstrating that, whereas acquired resistance may be reversed, changes in kinase activation and metastatic potential are unidirectional associated with tumor progression.
Alfredo A Molinolo - One of the best experts on this subject based on the ideXlab platform.
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progestin and Antiprogestin responsiveness in breast cancer is driven by the pra prb ratio via aib1 or smrt recruitment to the ccnd1 and myc promoters
International Journal of Cancer, 2015Co-Authors: Victoria Wargon, Sebastián Giulianelli, Marina Riggio, Gonzalo Ricardo Sequeira, Paola Alejandra Rojas, Maria May, Maria Laura Polo, Maria Alicia Gorostiaga, Britta M Jacobsen, Alfredo A MolinoloAbstract:There is emerging interest in understanding the role of progesterone receptors (PRs) in breast cancer. The aim of this study was to investigate the proliferative effect of progestins and Antiprogestins depending on the relative expression of the A (PRA) and B (PRB) isoforms of PR. In mifepristone (MFP)-resistant murine carcinomas Antiprogestin responsiveness was restored by re-expressing PRA using demethylating agents and histone deacetylase inhibitors. Consistently, in two human breast cancer xenograft models, one manipulated to overexpress PRA or PRB (IBH-6 cells), and the other expressing only PRA (T47D-YA) or PRB (T47D-YB), MFP selectively inhibited the growth of PRA-overexpressing tumors and stimulated IBH-6-PRB xenograft growth. Furthermore, in cells with high or equimolar PRA/PRB ratios, which are stimulated to proliferate in vitro by progestins, and are inhibited by MFP, MPA increased the interaction between PR and the coactivator AIB1, and MFP favored the interaction between PR and the corepressor SMRT. In a PRB-dominant context in which MFP stimulates and MPA inhibits cell proliferation, the opposite interactions were observed. Chromatin immunoprecipitation assays in T47D cells in the presence of MPA or MFP confirmed the interactions between PR and the coregulators at the CCND1 and MYC promoters. SMRT downregulation by siRNA abolished the inhibitory effect of MFP on MYC expression and cell proliferation. Our results indicate that Antiprogestins are therapeutic tools that selectively inhibit PRA-overexpressing tumors by increasing the SMRT/AIB1 balance at the CCND1 and MYC promoters.
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reversal of Antiprogestin resistance and progesterone receptor isoform ratio in acquired resistant mammary carcinomas
Breast Cancer Research and Treatment, 2009Co-Authors: Victoria Wargon, Paola Rojas, Alfredo A Molinolo, Luisa A Helguero, Julieta Bolado, Virginia Novaro, Claudia LanariAbstract:To explore mechanisms related to hormone resistance, three resistant variants of the MPA mouse breast cancer tumor model with low levels of progesterone receptor (PR) isoform A (PR-A)/high PR-B expression were developed by prolonged selective pressure with Antiprogestins. The resistant phenotype of one tumor line was reversed spontaneously after several consecutive passages in syngeneic BALB/c mice or by 17-β-estradiol or tamoxifen treatment, and this reversion was significantly associated with an increase in PR-A expression. The responsive parental tumors disclosed low activation of ERK and high activation of AKT; resistant tumors on the other hand, showed the opposite, and this was associated with a higher metastatic potential, that did not revert. This study shows for the first time in vivo a relationship between PR isoform expression and Antiprogestin responsiveness, demonstrating that, whereas acquired resistance may be reversed, changes in kinase activation and metastatic potential are unidirectional associated with tumor progression.
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p21, p27 and p53 in estrogen and Antiprogestin-induced tumor regression of experimental mouse mammary ductal carcinomas
Carcinogenesis, 2002Co-Authors: Silvia Vanzulli, Luisa A Helguero, Alejo Efeyan, Fernando Benavides, Giselle Peters, Jianjun Shen, Claudio J. Conti, Claudia Lee Malvina Lanari, Alfredo A MolinoloAbstract:Metastatic mammary carcinoma tumor lines 59-2-HI and C7-2-HI originated in female BALB/c mice treated with medroxyprogesterone acetate and are maintained by syngeneic transplantation. Both lines express estrogen (ER) and progesterone receptors (PR) and regress completely after estradiol (E 2 ) or Antiprogestin treatment. The BET tumor line, of similar origin and biological features, regresses only after E 2 treatment. To investigate possible differences between E 2 - and Antiprogestin-mediated effects we evaluated the morphological features, mitosis and apoptosis, and the differential expression of cell-cycle inhibitors associated with tumor regression. Treatments started when tumors reached 50-100 mm 2 . After 24-96 h, tumors were excised and processed for morphological and immunohistochemical studies. Regression was associated with a significant and early decrease in the number of mitosis and with higher percentages of apoptotic cells. These phenomena were accompanied by an increase in p21 and p27 expression in the E 2 and Antiprogestin-responsive lines treated with E 2 , RU 38.486 or ZK 98.299 (P < 0.05). In BET tumors treated with E 2 , p21 expression remained within basal levels and only p27 increased (P < 0.05). p53 was low in control 59-2-HI and C7-2-HI tumors and increased after treatment (P < 0.05) whereas BET untreated tumors already expressed high levels of p53 and MDM2. Although the immunohistochemical findings were compatible with alterations of p53, SSCP evaluation failed to disclose the presence of mutations, suggesting that the defective expression of p21 is related to an impaired p53 pathway. UV irradiation failed to increase p21 expression in BET, but was able to induce p53 and p21 in 59-2-HI and C7-2-HI tumors. The absence of an increased expression of p21 in E 2 -regressing BET lesions suggests that this protein is not necessary for estrogen-induced regression, but may be essential for Antiprogestin action. Our results also suggest that p53/MDM2 alterations may be one of the mechanisms responsible for selected hormone resistance in breast carcinomas.
Paul F.a. Van Look - One of the best experts on this subject based on the ideXlab platform.
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Antiprogestins for contraception
Seminars in reproductive medicine, 2005Co-Authors: Helena Von Hertzen, Paul F.a. Van LookAbstract:Antiprogestins could be a very promising group of compounds for contraception because they counteract the effects of progesterone, a key hormone for normal reproductive functioning. Great efforts have therefore been devoted to testing various ways of using these compounds for family planning. Most of this work has involved mifepristone; other Antiprogestins have not been available for trials. With a few exceptions, the outcome of the studies performed to date has not met expectations. The most promising approaches seem to be the use of Antiprogestins for emergency contraception, perhaps also as a daily pill when the dose is high enough to block ovulation, and in sequential regimens followed by a progestin. Given that Antiprogestins differ in their affinity for target organs, better results could possibly be achieved by using more specific compounds than mifepristone. It is hoped that a wider choice of antiprogestational compounds will soon become available for research.
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Effects of two Antiprogestins on early pregnancy in the long-tailed macaque (Macaca fascicularis)
Contraception, 1996Co-Authors: Alice F. Tarantal, Andrew G Hendrickx, Stephen A. Matlin, Bill L. Lasley, Charles A.a. Thomas, Pamela M. Vince, Paul F.a. Van LookAbstract:The abortifacient effects of mifepristone and HRP 2000 were compared in gravid long-tailed macaques. Thirty-six animals were studied with treatment administered either by the oral (0.5 or 5.0 mg/kg; N = 5 per Antiprogestin per dose) or intramuscular (i.m.) routes (0.5 mg/kg; N = 5 per Antiprogestin) on gestational days (GD) 23-26; six vehicle controls were included. Blood samples were collected for assay of progesterone (P4) and each of the Antiprogestins (pre-treatment, daily GD 23-28, every other day GD 30-40), and animals were monitored sonographically throughout gestation. Results of these studies indicated high rates of abortion with i.m. administration (3/5 mifepristone, 4/5 HRP 2000) and 5.0 mg/kg oral route (4/5, 2/5, respectively), with less effects noted at oral doses of 0.5 mg/kg (2/5, 0/5, respectively). No early abortions were observed in the control groups. Following daily i.m. treatment, peak levels of 8-16 ng/ml mifepristone were detected whereas 6-10 ng/ ml of HRP 2000 were noted (GD 26-27). No serum levels of mifepristone were detected following either of the oral doses whereas serum levels of 2-6 ng/ml HRP 2000 were noted with high dose oral administratation. Results of these studies suggest: (1) both Antiprogestins are roughly comparable in terminating early pregnancy although HRP 2000 may be more efficacious when administered i.m. whereas mifepristone may be more effective when administered orally; (2) similar levels of biological activity are seen with the i.m. and high dose oral dosing regimens, with little or no activity with the oral low dose; and (3) infants resulting from surviving pregnancies were not affected by early gestation exposure.
Mary B. Zelinski-wooten - One of the best experts on this subject based on the ideXlab platform.
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Chronic low-dose Antiprogestin impairs preimplantation embryogenesis, but not oocyte nuclear maturation or fertilization in rhesus monkeys
Steroids, 2003Co-Authors: Sherri M. Borman, Kristof Chwalisz, Richard L. Stouffer, Mary B. Zelinski-wootenAbstract:Continual administration of low doses of the Antiprogestin ZK 137 316 permits ovarian/menstrual cyclicity, but prevents pregnancy in female rhesus monkeys. The sites of contraceptive action remain unknown. This study determined whether chronic, low-dose Antiprogestin exposure during follicular development impairs oocyte maturation in vivo, as well as fertilization and preimplantation embryogenesis in vitro. Adult, female rhesus monkeys exhibiting normal menstrual cycles received vehicle (n = 9) or 0.03 mg ZK 137 316 (n = 8)/kg body weight i.m. daily for 3 months. Controlled ovarian stimulation with recombinant gonadotropins was initiated in the 3rd month. Oocytes collected from preovulatory follicles were evaluated for nuclear maturity and inseminated in vitro. Preimplantation embryonic development was monitored in vitro. The total number of oocytes and percentage collected at each nuclear stage were similar in both groups. More (P < 0.05) atretic oocytes were recovered following Antiprogestin relative to vehicle treatment. Fertilization rates and percentages of embryos that progressed to the morula stage were similar between groups, but Antiprogestin-treated females exhibited less (P < 0.05) normal cleavage. Embryonic development was accelerated by 1 day (P < 0.05) from the 16-cell to the morula stage in the Antiprogestin group relative to vehicle. Despite this, the majority of embryos became blastocysts within 6 days in vitro in the Antiprogestin group, but fewer expanded (P = 0.09) and hatched (P < 0.05) compared to vehicle. During in vivo treatment with chronic, low-dose Antiprogestin, oocytes retained their ability to resume and complete meiosis as well as fertilize following insemination in vitro. However, preimplantation embryogenesis in vitro was impaired, particularly during the later stages of blastocyst development. Thus, Antiprogestin exposure during follicular development altered oocyte functions that are critical for normal preimplantation embryogenesis; this may contribute to pregnancy prevention.
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Chronic low-dose Antiprogestin impairs preimplantation embryogenesis, but not oocyte nuclear maturation or fertilization in rhesus monkeys.
Steroids, 2003Co-Authors: Sherri M. Borman, Kristof Chwalisz, Richard L. Stouffer, Mary B. Zelinski-wootenAbstract:Continual administration of low doses of the Antiprogestin ZK137316 permits ovarian/menstrual cyclicity, but prevents pregnancy in female rhesus monkeys. The sites of contraceptive action remain unknown. This study determined whether chronic, low-dose Antiprogestin exposure during follicular development impairs oocyte maturation in vivo, as well as fertilization and preimplantation embryogenesis in vitro. Adult, female rhesus monkeys exhibiting normal menstrual cycles received vehicle (n=9) or 0.03 mg ZK137316 (n=8)/kg body weight i.m. daily for 3 months. Controlled ovarian stimulation with recombinant gonadotropins was initiated in the 3rd month. Oocytes collected from preovulatory follicles were evaluated for nuclear maturity and inseminated in vitro. Preimplantation embryonic development was monitored in vitro. The total number of oocytes and percentage collected at each nuclear stage were similar in both groups. More (P