RESUMO
The development of antiprogestins was initially a gynecological purpose. However, since mifepristone was developed, its application for breast cancer treatment was immediately proposed. Later, new compounds with lower antiglucocorticoid and antiandrogenic effects were developed to be applied to different pathologies, including breast cancer. We describe herein the studies performed in the breast cancer field with special focus on those reported in recent years, ranging from preclinical biological models to those carried out in patients. We highlight the potential use of antiprogestins in breast cancer prevention in women with BRCA1 mutations, and their use for breast cancer treatment, emphasizing the need to elucidate which patients will respond. In this sense, the PR isoform ratio has emerged as a possible tool to predict antiprogestin responsiveness. The effects of combined treatments of antiprogestins together with other drugs currently used in the clinic, such as tamoxifen, CDK4/CDK6 inhibitors or pembrolizumab in preclinical models is discussed since it is in this scenario that antiprogestins will be probably introduced. Finally, we explain how transcriptomic or proteomic studies, that were carried out in different luminal breast cancer models and in breast cancer samples that responded or were predicted to respond to the antiprogestin therapy, show a decrease in proliferative pathways. Deregulated pathways intrinsic of each model are discussed, as well as how these analyses may contribute to a better understanding of the mechanisms involved.
Assuntos
Neoplasias da Mama , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Feminino , Receptores de Progesterona/metabolismo , Animais , Mifepristona/uso terapêutico , Mifepristona/farmacologia , Antagonistas de Hormônios/uso terapêuticoRESUMO
Progesterone receptors (PRs) are biomarkers used as prognostic and predictive factors in breast cancer, but they are still not used as therapeutic targets. We have proposed that the ratio between PR isoforms A and B (PRA and PRB) predicts antiprogestin responsiveness. The MIPRA trial confirmed the benefit of 200 mg mifepristone, administered to patients with tumors with a high PRA/PRB ratio, but dose-ranging has not been conducted. The aim of this study was to establish the plasma mifepristone levels of patients from the MIPRA trial, along with the resultant steroid profiles, and compare these with those observed in mifepristone-treated mice using therapeutic schemes able to induce the regression of experimental mammary carcinomas with high PRA/PRB ratios: 6 mg pellets implanted subcutaneously, or daily doses of 12 mg/kg body weight. The plasma levels of mifepristone and other 19 plasma steroids were measured by liquid chromatography-tandem mass spectometry. In mifepristone-treated mice, plasma levels were lower than those registered in mifepristone-treated patients (i.e. day 7 after treatment initiation, pellet-treated mice: 8.4 ± 3.9 ng/mL; mifepristone-treated patients: 300.3 ± 31.7 ng/mL (mean ± s.d.; P < 0.001)). The increase in corticoid related steroids observed in patients was not observed in mifepristone-treated mice. The increase in progesterone levels was the most significant side effect detected in mifepristone-treated mice after 14 or 21 days of treatment, probably due to an ovarian compensatory effect not observed in postmenopausal patients. We conclude that in future clinical trials using mifepristone, the possibility of lowering the standard daily dose of 200 mg should be considered.
Assuntos
Neoplasias da Mama , Mifepristona , Humanos , Camundongos , Animais , Feminino , Mifepristona/uso terapêutico , Mifepristona/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Receptores de Progesterona , Antagonistas de Hormônios/uso terapêutico , Antagonistas de Hormônios/farmacologia , PrognósticoRESUMO
Luminal breast cancer (BrCa) has a favorable prognosis compared with other tumor subtypes. However, with time, tumors may evolve and lead to disease progression; thus, there is a great interest in unraveling the mechanisms that drive tumor metastasis and endocrine resistance. In this review, we focus on one of the many pathways that have been involved in tumor progression, the fibroblast growth factor/fibroblast growth factor receptor (FGFR) axis. We emphasize in data obtained from in vivo experimental models that we believe that in luminal BrCa, tumor growth relies in a crosstalk with the stromal tissue. We revisited the studies that illustrate the interaction between hormone receptors and FGFR. We also highlight the most frequent alterations found in BrCa cell lines and provide a short review on the trials that use FGFR inhibitors in combination with endocrine therapies. Analysis of these data suggests there are many players involved in this pathway that might be also targeted to decrease FGF signaling, in addition to specific FGFR inhibitors that may be exploited to increase their efficacy.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Fatores de Crescimento de Fibroblastos/fisiologia , Receptores de Fatores de Crescimento de Fibroblastos/fisiologia , Receptores de Esteroides/fisiologia , Transdução de Sinais/fisiologia , Animais , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/química , Neoplasias da Mama/terapia , Linhagem Celular Tumoral , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Receptor alfa de Estrogênio/análise , Feminino , Fatores de Crescimento de Fibroblastos/genética , Amplificação de Genes , Humanos , Camundongos , Mutação , Receptor Cross-Talk/fisiologia , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Receptores de Fatores de Crescimento de Fibroblastos/genéticaRESUMO
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.
Assuntos
Neoplasias da Mama , Proteínas de Ciclo Celular , Peptídeos e Proteínas de Sinalização Intracelular , Receptores de Progesterona , Animais , Neoplasias da Mama/patologia , Proteínas de Ciclo Celular/metabolismo , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Metástase Neoplásica , Progesterona/farmacologia , Progestinas/metabolismo , Isoformas de Proteínas/metabolismo , Receptores de Progesterona/metabolismoRESUMO
Session 1: Tumor heterogeneity and breast cancer therapy. Session 2: From hormone receptors to the immune system: the evolution of therapeutic targets in breast cancer. Session 3: Cancer stem cells and de-differentiated phenotype. Session 4: Mouse models for studying breast cancer initiation and progression. Session 5: Round Table 1 - Genomics Platforms. Session 6: Genetics and Epigenetics of Breast Cancer. Session 7: Understanding the metastatic cascade to learn how to inhibit tumor progression. Session 8: Round Table 2 - Biorepositories and sample management. Session 9: Estrogen receptors: their involvement in endocrine resistance and dormancy. Session 10: Novel targets in the era of precision medicine. Session 11: Round Table 3 - Interaction among government, non-government agencies, and industry for funding and promoting breast cancer translational research. Session 12: Local and systemic therapies. Session 13: New developments in diagnosis and epidemiology of breast cancer.
Assuntos
Neoplasias , Receptores de Estrogênio , Animais , Feminino , CamundongosRESUMO
The first Buenos Aires Breast Cancer Symposium (BA-BCS) was held in a virtual format, between the 17th and the 21st of May 2021. The main goal of the meeting was to facilitate the interaction among physicians and basic researchers from South America and with peers from the rest of the world. To embrace their different interests and concerns, the congress included not only talks on basic, translational and clinical research, but also round tables to discuss diagnostic methods, research financing and biobank management, as well as virtual poster sessions in which the youngest fellows presented their recent findings. This report provides a brief overview of the talks delivered during the meeting, which addressed a wide variety of vital issues for breast cancer research mostly focused on the accurate diagnosis, prevention and treatment of this illness. The presentations included a wide spectrum of themes including hormone receptors and the relevance of their mutations, immunotherapy, cancer stem cells, mouse models, environmental hazards, genetics and epigenetics, local and systemic therapies, liquid biopsies, the metastatic cascade, therapy resistance and dormancy, among others.
Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/terapia , Ensaios Clínicos como Assunto , Pesquisa Translacional Biomédica , Argentina , Feminino , Humanos , Cooperação Internacional , Relações InterprofissionaisRESUMO
Progesterone receptors (PR) play a pivotal role in many female reproductive tissues such as the uterus, the ovary, and the mammary gland (MG). Moreover, PR play a key role in breast cancer growth and progression. This has led to the development and study of different progestins and antiprogestins, many of which are currently being tested in clinical trials for cancer treatment. Recent reviews have addressed the role of PR in MG development, carcinogenesis, and breast cancer growth. Thus, in this review, in addition to making an overview on PR action in normal and tumor breast, the focus has been put on highlighting the still unresolved topics on hormone treatment involving PR isoforms and breast cancer prognosis.