Research Interests: KEGG and Mifepristone
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Since antiprogestins inhibit the growth of preclinical mammary tumor models expressing higher levels of progesterone receptor (PR) isoform A (PRA) than isoform B (PRB), we designed a window-of-opportunity trial (MIPRA; NCT02651844) to... more
Since antiprogestins inhibit the growth of preclinical mammary tumor models expressing higher levels of progesterone receptor (PR) isoform A (PRA) than isoform B (PRB), we designed a window-of-opportunity trial (MIPRA; NCT02651844) to study the benefits of mifepristone (MFP) in luminal breast carcinomas from postmenopausal patients selected by their PR+ expression (>50%) and their PR isoform ratio (PRA/PRB>1.5; PRA-H). A decrease in the cell proliferation marker Ki67 was registered after treatment in 14 out of the 20 tumors evaluated. This inhibition was associated with a decrease in PR, estrogen receptor (ER) and pSer118ER evaluated by immunohistochemistry while no changes in pSer167ER expression were observed (PMID: 36269797). In selected tissues from these samples we observed that the staining intensity in trapped glands within the MFP-treated tumors did not follow a similar trend as that of tumor cells. Thus, the aim of this study was to evaluate the expression of hormone ...
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Morphological evaluation of CNBs and matched surgical samples; RNA-Seq analysis; Proteomics
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Morphological features of tumors before and after mifepristone treatment
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Morphological features after mifepristone treatment. A-D, Images illustrating increased stromal tissue (A), thin and scarce collagen fibers, and increased stromal matrix (arrow; B), an area of tissue remodeling (C), and an area of... more
Morphological features after mifepristone treatment. A-D, Images illustrating increased stromal tissue (A), thin and scarce collagen fibers, and increased stromal matrix (arrow; B), an area of tissue remodeling (C), and an area of increased differentiation (D) observed in the surgical samples (S) compared to the respective core needle biopsies (CNB). E, Image illustrates an area of necrosis (dotted arrow) together with a differentiated structure (black arrow) in a surgical sample. F, Cells with Alcian blue+ (left), PAS+ (middle) and MUC-1+ (immunohistochemistry; right) vacuoles observed in a mifepristone-treated tumor. Inset: High power field of a differentiated gland/duct.
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Purpose:Preclinical data suggest that antiprogestins inhibit the growth of luminal breast carcinomas that express higher levels of progesterone receptor isoform A (PRA) than isoform B (PRB). Thus, we designed a presurgical window of... more
Purpose:Preclinical data suggest that antiprogestins inhibit the growth of luminal breast carcinomas that express higher levels of progesterone receptor isoform A (PRA) than isoform B (PRB). Thus, we designed a presurgical window of opportunity trial to determine the therapeutic effects of mifepristone in patients with breast cancer, based on their high PRA/PRB isoform ratio (MIPRA; NCT02651844).Patients and Methods:Twenty patients with luminal breast carcinomas with PRA/PRB > 1.5 (determined by Western blots), and PR ≥ 50%, naïve from previous treatment, were included for mifepristone treatment (200 mg/day orally; 14 days). Core needle biopsies and surgical samples were formalin fixed for IHC studies, while others were snap-frozen to perform RNA sequencing (RNA-seq), proteomics, and/or Western blot studies. Plasma mifepristone levels were determined using mass spectrometry. The primary endpoint was the comparison of Ki67 expression pretreatment and posttreatment.Results:A 49.62%...
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Representativeness of Study Participants
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Mutations identified in RNA-Seq analysis. The data obtained in RNA-Seq studies were graphed using the Oviz-Bio tool (https://academic.oup.com/nar/article/48/W1/W415/5835823). Only driver breast cancer genes (99) were selected from the... more
Mutations identified in RNA-Seq analysis. The data obtained in RNA-Seq studies were graphed using the Oviz-Bio tool (https://academic.oup.com/nar/article/48/W1/W415/5835823). Only driver breast cancer genes (99) were selected from the Intogene data base (https://www.intogen.org/download) and we found mutations in 19 driver genes after read depth filtering (DP >50). Of note is the missense mutation found in ESR1 in the M070 patient. Left, Percentage of samples with mutations. Color defines the type of mutations.
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A, Library size before and after low count filtering. B, P-value histogram distribution observed in the differential expression analysis. C, Pairwise scatter plots of the first five principal components from the principal component... more
A, Library size before and after low count filtering. B, P-value histogram distribution observed in the differential expression analysis. C, Pairwise scatter plots of the first five principal components from the principal component analysis of RNA-Seq data.
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RNA-Seq Variant calling
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Mifepristone plasma levels and mifepristone-related side effects. A, Plasma levels of mifepristone 7 or 14 days after mifepristone treatment. The data from 9-10 patients are shown. Data were analyzed with ANOVA for matched samples... more
Mifepristone plasma levels and mifepristone-related side effects. A, Plasma levels of mifepristone 7 or 14 days after mifepristone treatment. The data from 9-10 patients are shown. Data were analyzed with ANOVA for matched samples (Friedman test). B, Clinical adverse effects grade 1 recorded in mifepristone (MFP)-treated patients. C, Laboratory values. Patients M049, M095 and M140 were treated for diabetes. Patients M009, M019, M023, M042, M049, M062, M070, M077, M090, M095, M105 and M140 were treated for hypertension and patients M009, M019 and M124 were treated for hypothyroidism. Dotted areas represent normal levels. Patients under mifepristone treatment did not interrupt standard medicine care.
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Proteomics: DE and Reactome of Cyt proteins
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RNA-Seq DEG and GSEA
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Proteomics: Enrichment analysis from heatmap
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A, Prevailing PR isoforms before and after mifepristone treatment and their prevailing nuclear (Nuc) or cytosolic (Cyt) localization in western blot studies. *: Prevailing PR isoforms in Western blot studies; #: Distribution of PR in the... more
A, Prevailing PR isoforms before and after mifepristone treatment and their prevailing nuclear (Nuc) or cytosolic (Cyt) localization in western blot studies. *: Prevailing PR isoforms in Western blot studies; #: Distribution of PR in the Nuc or Cyt compartments; CNB: Core needle biopsy, S: Surgical sample. In grey font: Mifepristone unresponsive tumors by Ki67 criteria. B, Representative western blots of CNB and surgical samples from all patients. The upper band is PRB and the lower band PRA, as labeled in the first set.
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Evaluation of Ki67 expression in paired samples before and after mifepristone treatment by two independent pathologists, and time elapsed between core needle biopsy and surgery.
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Purpose:Preclinical data suggest that antiprogestins inhibit the growth of luminal breast carcinomas that express higher levels of progesterone receptor isoform A (PRA) than isoform B (PRB). Thus, we designed a presurgical window of... more
Purpose:Preclinical data suggest that antiprogestins inhibit the growth of luminal breast carcinomas that express higher levels of progesterone receptor isoform A (PRA) than isoform B (PRB). Thus, we designed a presurgical window of opportunity trial to determine the therapeutic effects of mifepristone in patients with breast cancer, based on their high PRA/PRB isoform ratio (MIPRA; NCT02651844).Patients and Methods:Twenty patients with luminal breast carcinomas with PRA/PRB > 1.5 (determined by Western blots), and PR ≥ 50%, naïve from previous treatment, were included for mifepristone treatment (200 mg/day orally; 14 days). Core needle biopsies and surgical samples were formalin fixed for IHC studies, while others were snap-frozen to perform RNA sequencing (RNA-seq), proteomics, and/or Western blot studies. Plasma mifepristone levels were determined using mass spectrometry. The primary endpoint was the comparison of Ki67 expression pretreatment and posttreatment.Results:A 49.62%...
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Background: Preclinical data suggests that antiprogestins inhibit the growth of luminal breast carcinomas expressing higher levels of progesterone receptor isoform A (PRA) than isoform B (PRB). Thus, we designed a pre-surgical window of... more
Background: Preclinical data suggests that antiprogestins inhibit the growth of luminal breast carcinomas expressing higher levels of progesterone receptor isoform A (PRA) than isoform B (PRB). Thus, we designed a pre-surgical window of opportunity trial to determine the therapeutic effects of oral mifepristone (MFP) in 20 breast cancer patients selected by their high PRA/PRB isoform ratio (MIPRA; NCT02651844).Methods. MIPRA is an open-label, one-arm, prospective interventional study. After the selection process, 20 patients that met the inclusion criteria, with ER+, PRA/PRB>1.5 determined by Western blots, and total PR ≥50% determined by immunohistochemistry (IHC), were included for daily MFP treatment (200 mg/day p.o., 14 days). Core needle biopsies and surgical samples were formalin-fixed for IHC studies, and others were snap-frozen for further molecular studies. Besides, plasma samples were obtained for MFP dosing by LC-MS/MS. RNA was extracted from frozen tissue with a colum...
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Progesterone receptors (PRs) ligands are being tested in luminal breast cancer. There are mainly two PR isoforms, PRA and PRB, and their ratio (PRA/PRB) may be predictive of antiprogestin response. Our aim was to investigate: the impact... more
Progesterone receptors (PRs) ligands are being tested in luminal breast cancer. There are mainly two PR isoforms, PRA and PRB, and their ratio (PRA/PRB) may be predictive of antiprogestin response. Our aim was to investigate: the impact of the PR isoform ratio on metastatic behaviour, the PR isoform ratio in paired primary tumours and lymph node metastases (LNM) and, the effect of antiprogestin/progestins on metastatic growth. Using murine and human metastatic models, we demonstrated that tumours with PRB > PRA (PRB‐H) have a higher proliferation index but less metastatic ability than those with PRA > PRB (PRA‐H). Antiprogestins and progestins inhibited metastatic burden in PRA‐H and PRB‐H models, respectively. In breast cancer samples, LNM retained the same PRA/PRB ratio as their matched primary tumours. Moreover, PRA‐H LNM expressed higher total PR levels than the primary tumours. The expression of NDRG1, a metastasis suppressor protein, was higher in PRB‐H compared to PRA‐H tumours and was inversely regulated by antiprogestins/progestins. The binding of the corepressor SMRT at the progesterone responsive elements of the NDRG1 regulatory sequences, together with PRA, impeded its expression in PRA‐H cells. Antiprogestins modulate the interplay between SMRT and AIB1 recruitment in PRA‐H or PRB‐H contexts regulating NDRG1 expression and thus, metastasis. In conclusion, we provide a mechanistic interpretation to explain the differential role of PR isoforms in metastatic growth and highlight the therapeutic benefit of using antiprogestins in PRA‐H tumours. The therapeutic effect of progestins in PRB‐H tumours is suggested.
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Background: Different antiprogestins have been clinically evaluated in gynecological andbreast cancers. Mifepristone (MFP), as well as onapristone and telapristone acetate, showedpartial responses in breast cancer clinical trials.... more
Background: Different antiprogestins have been clinically evaluated in gynecological andbreast cancers. Mifepristone (MFP), as well as onapristone and telapristone acetate, showedpartial responses in breast cancer clinical trials. Preclinical data indicates that antiprogestinsinhibit cell proliferation of luminal breast carcinomas expressing higher levels of progesteronereceptor isoform A (PRA) than those of isoform B (PRB) evaluated by western blots (WB). Thus,we designed a pre-surgical window trial to determine the therapeutic effects of oral MFP oncell proliferation and on differential gene expression in 20 breast cancer patients selected bytheir high PRA/PRB isoform ratio.Methods. MIPRA is an open-label, one-arm, prospective interventional study (NCT02651844).We interviewed 140 naive breast cancer patients and 133 accepted to participate. Four coreultrasound-guided biopsies were performed, two were formalin-fixed for diagnosis, ER, PR,HER2, and Ki67 evaluation and two were snap-...
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Seventy percent of breast cancers express estrogen (ER) and progesterone receptors (PR) and respond to antiestrogen therapies. Emerging evidence from experimental studies and human epidemiology, points to a relevant role for progestins in... more
Seventy percent of breast cancers express estrogen (ER) and progesterone receptors (PR) and respond to antiestrogen therapies. Emerging evidence from experimental studies and human epidemiology, points to a relevant role for progestins in breast carcinogenesis and cancer growth. Others and we have proposed that there is a role for antiprogestins in the therapeutic armamentarium, but the challenge remains to identify which patients would benefit from targeting the PR in addition to ER. Preclinical data indicates that antiprogestins block cell proliferation and increase apoptosis only in ER+ breast cancers expressing levels of PRA higher than those of PRB. The aim of this study is to evaluate the therapeutic effects of Mifepristone (MFP) on breast cancer patients selected by their PRA/PRB isoform ratio, for 14 days in between core biopsy and surgery (MIPRA trial ClinicalTrials.gov Identifier: NCT02651844). Methods: This is an open label, interventional with single group assignment stu...
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Near 75 percent of breast cancer patients express progesterone (PR) and estrogen (ER) receptors and are potential candidates to receive an endocrine therapy. Most of the endocrine therapies available have been designed to target ER and... more
Near 75 percent of breast cancer patients express progesterone (PR) and estrogen (ER) receptors and are potential candidates to receive an endocrine therapy. Most of the endocrine therapies available have been designed to target ER and there is not much information about PR as a therapeutic target for breast cancer treatment. However, extensive clinical and experimental evidence suggest that progestins are associated with the induction and maintenance of the neoplastic phenotype in the mammary gland. Moreover, different antiprogestins including ZK 98299, ZK 230211 and RU-486 proved to exert excellent therapeutic effects in murine mammary carcinomas from the MPA-breast cancer model which express high levels of PR with an increased PR-isoform A/PR-isoform B ratio (PR-A/PR-B) (Lanari C et al, Endocrine Related Cancer, 2009 Feb, Jun;16(2):333-50). The main goal of this study is to validate these experimental results using human breast cancer samples and to identify breast cancer patient...
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Proteomics: DE and Reactome of Nuc proteins