RESUMEN
BACKGROUND: Genetic abnormalities in the FGFR signalling occur in 40% of breast cancer (BCa) patients resistant to anti-ER therapy, which emphasizes the potential of FGFR-targeting strategies. Recent findings indicate that not only mutated FGFR is a driver of tumour progression but co-mutational landscapes and other markers should be also investigated. Autophagy has been recognized as one of the major mechanisms underlying the role of tumour microenvironment in promotion of cancer cell survival, and resistance to anti-ER drugs. The selective autophagy receptor p62/SQSTM1 promotes Nrf-2 activation by Keap1/Nrf-2 complex dissociation. Herein, we have analysed whether the negative effect of FGFR2 on BCa cell response to anti-ER treatment involves the autophagy process and/or p62/Keap1/Nrf-2 axis. METHODS: The activity of autophagy in ER-positive MCF7 and T47D BCa cell lines was determined by analysis of expression level of autophagy markers (p62 and LC3B) and monitoring of autophagosomes' maturation. Western blot, qPCR and proximity ligation assay were used to determine the Keap1/Nrf-2 interaction and Nrf-2 activation. Analysis of 3D cell growth in Matrigel® was used to assess BCa cell response to applied treatments. In silico gene expression analysis was performed to determine FGFR2/Nrf-2 prognostic value. RESULTS: We have found that FGFR2 signalling induced autophagy in AMPKα/ULK1-dependent manner. FGFR2 activity promoted dissociation of Keap1/Nrf-2 complex and activation of Nrf-2. Both, FGFR2-dependent autophagy and activation of Nrf-2 were found to counteract the effect of anti-ER drugs on BCa cell growth. Moreover, in silico analysis showed that high expression of NFE2L2 (gene encoding Nrf-2) combined with high FGFR2 expression was associated with poor relapse-free survival (RFS) of ER+ BCa patients. CONCLUSIONS: This study revealed the unknown role of FGFR2 signalling in activation of autophagy and regulation of the p62/Keap1/Nrf-2 interdependence, which has a negative impact on the response of ER+ BCa cells to anti-ER therapies. The data from in silico analyses suggest that expression of Nrf-2 could act as a marker indicating potential benefits of implementation of anti-FGFR therapy in patients with ER+ BCa, in particular, when used in combination with anti-ER drugs.
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Autofagia , Neoplasias de la Mama , Proteína 1 Asociada A ECH Tipo Kelch , Factor 2 Relacionado con NF-E2 , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos , Femenino , Humanos , Autofagia/efectos de los fármacos , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/genética , Células MCF-7 , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/metabolismo , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Proteína Sequestosoma-1/metabolismo , Proteína Sequestosoma-1/genética , Transducción de Señal/efectos de los fármacos , Antagonistas de Estrógenos/farmacología , Moduladores de los Receptores de Estrógeno/farmacologíaRESUMEN
Gonadal hormone deprivation (GHD) and decline such as menopause and bilateral oophorectomy are associated with an increased risk of neurodegeneration. Yet, hormone therapies (HTs) show varying efficacy, influenced by factors such as sex, drug type, and timing of treatment relative to hormone decline. We hypothesize that the molecular environment of the brain undergoes a transition following GHD, impacting the effectiveness of HTs. Using a GHD model in mice treated with Tibolone, we conducted proteomic analysis and identified a reprogrammed response to Tibolone, a compound that stimulates estrogenic, progestogenic, and androgenic pathways. Through a comprehensive network pharmacological workflow, we identified a reprogrammed response to Tibolone, particularly within "Pathways of Neurodegeneration", as well as interconnected pathways including "cellular respiration", "carbon metabolism", and "cellular homeostasis". Analysis revealed 23 proteins whose Tibolone response depended on GHD and/or sex, implicating critical processes like oxidative phosphorylation and calcium signalling. Our findings suggest the therapeutic efficacy of HTs may depend on these variables, suggesting a need for greater precision medicine considerations whilst highlighting the need to uncover underlying mechanisms.
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Norpregnenos , Animales , Norpregnenos/farmacología , Femenino , Ratones , Proteómica/métodos , Moduladores de los Receptores de Estrógeno/farmacología , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/tratamiento farmacológico , Ratones Endogámicos C57BL , Masculino , Ovariectomía , Hormonas Gonadales/metabolismo , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/patologíaRESUMEN
High throughput transcriptomics (HTTr) profiling has the potential to rapidly and comprehensively identify molecular targets of environmental chemicals that can be linked to adverse outcomes. We describe here the construction and characterization of a 50-gene expression biomarker designed to identify estrogen receptor (ER) active chemicals in HTTr datasets. Using microarray comparisons, the genes in the biomarker were identified as those that exhibited consistent directional changes when ER was activated (4 ER agonists; 4 ESR1 gene constitutively active mutants) and opposite directional changes when ER was suppressed (4 antagonist treatments; 4 ESR1 knockdown experiments). The biomarker was evaluated as a predictive tool using the Running Fisher algorithm by comparison to annotated gene expression microarray datasets including those evaluating the transcriptional effects of hormones and chemicals in MCF-7 cells. Depending on the reference dataset used, the biomarker had a predictive accuracy for activation of up to 96%. To demonstrate applicability for HTTr data analysis, the biomarker was used to identify ER activators in a set of 15 chemicals that are considered potential bisphenol A (BPA) alternatives examined at up to 10 concentrations in MCF-7 cells and analyzed by full-genome TempO-Seq. Using benchmark dose (BMD) modeling, the biomarker genes stratified the ER potency of BPA alternatives consistent with previous studies. These results demonstrate that the ER biomarker can be used to accurately identify ER activators in transcript profile data derived from MCF-7 cells.
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Compuestos de Bencidrilo , Fenoles , Receptores de Estrógenos , Humanos , Células MCF-7 , Receptores de Estrógenos/metabolismo , Receptores de Estrógenos/genética , Compuestos de Bencidrilo/toxicidad , Fenoles/farmacología , Fenoles/toxicidad , Perfilación de la Expresión Génica , Análisis de Secuencia por Matrices de Oligonucleótidos , Biomarcadores/metabolismo , Moduladores de los Receptores de Estrógeno/farmacologíaRESUMEN
Estrogen receptor positive (ER+) breast cancer is the most common breast cancer diagnosed annually in the US with endocrine-based therapy as standard-of-care for this breast cancer subtype. Endocrine therapy includes treatment with antiestrogens, such as selective estrogen receptor modulators (SERMs), selective estrogen receptor downregulators (SERDs), and aromatase inhibitors (AIs). Despite the appreciable remission achievable with these treatments, a substantial cohort of women will experience primary tumor recurrence, subsequent metastasis, and eventual death due to their disease. In these cases, the breast cancer cells have become resistant to endocrine therapy, with endocrine resistance identified as the major obstacle to the medical oncologist and patient. To combat the development of endocrine resistance, the treatment options for ER+, HER2 negative breast cancer now include CDK4/6 inhibitors used as adjuvants to antiestrogen treatment. In addition to the dysregulated activity of CDK4/6, a plethora of genetic and biochemical mechanisms have been identified that contribute to endocrine resistance. These mechanisms, which have been identified by lab-based studies utilizing appropriate cell and animal models of breast cancer, and by clinical studies in which gene expression profiles identify candidate endocrine resistance genes, are the subject of this review. In addition, we will discuss molecular targeting strategies now utilized in conjunction with endocrine therapy to combat the development of resistance or target resistant breast cancer cells. Of approaches currently being explored to improve endocrine treatment efficacy and patient outcome, two adaptive cell survival mechanisms, autophagy, and "reversible" senescence, are considered molecular targets. Autophagy and/or senescence induction have been identified in response to most antiestrogen treatments currently being used for the treatment of ER+ breast cancer and are often induced in response to CDK4/6 inhibitors. Unfortunately, effective strategies to target these cell survival pathways have not yet been successfully developed. Thus, there is an urgent need for the continued interrogation of autophagy and "reversible" senescence in clinically relevant breast cancer models with the long-term goal of identifying new molecular targets for improved treatment of ER+ breast cancer.
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Neoplasias de la Mama , Animales , Femenino , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Moduladores de los Receptores de Estrógeno/farmacología , Moduladores de los Receptores de Estrógeno/uso terapéutico , Resistencia a Antineoplásicos/genética , Recurrencia Local de Neoplasia/tratamiento farmacológico , Receptores de Estrógenos/metabolismo , AutofagiaRESUMEN
HER2-positive breast cancer is associated with aggressive behavior and reduced survival rates. Calcitriol restores the antiproliferative activity of antiestrogens in estrogen receptor (ER)-negative breast cancer cells by re-expressing ERα. Furthermore, calcitriol and its analog, EB1089, enhance responses to standard anti-cancer drugs. Therefore, we aimed to investigate EB1089 effects when added to the combined treatment of lapatinib and antiestrogens on the proliferation of HER2-positive breast cancer cells. BT-474 (ER-positive/HER2-positive) and SK-BR-3 (ER-negative/HER2-positive) cells were pre-treated with EB1089 to modulate ER expression. Then, cells were treated with EB1089 in the presence of lapatinib with or without the antiestrogens, and proliferation, phosphorylation array assays, and Western blot analysis were performed. The results showed that EB1089 restored the antiproliferative response to antiestrogens in SK-BR-3 cells and improved the inhibitory effects of the combination of lapatinib with antiestrogens in the two cell lines. Moreover, EB1089, alone or combined, modulated ERα protein expression and reduced Akt phosphorylation in HER2-positive cells. EB1089 significantly enhanced the cell growth inhibitory effect of lapatinib combined with antiestrogens in HER2-positive breast cancer cells by modulating ERα expression and Akt phosphorylation suppression. These results highlight the potential of this therapeutic approach as a promising strategy for managing HER2-positive breast cancer.
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Neoplasias de la Mama , Calcitriol/análogos & derivados , Humanos , Femenino , Lapatinib/farmacología , Lapatinib/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Calcitriol/farmacología , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Moduladores de los Receptores de Estrógeno/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor ErbB-2/metabolismo , Antagonistas de Estrógenos/uso terapéutico , Línea Celular TumoralRESUMEN
IMPORTANCE: There are no current data investigating the relationship between mesh-exposure complications after midurethral sling surgery and antiestrogen therapy. OBJECTIVES: We sought to determine if there are increased mesh-exposure complications between a breast cancer population versus a noncancer population particularly in conjunction with hormone suppression (HS) therapy. STUDY DESIGN: A retrospective chart review was performed on patients with a history of breast cancer undergoing tension-free vaginal tape (TVT) surgery at our institution between 2013 and 2021. A group of patients who underwent TVT surgery without a history of cancer served as our control. Univariate and multivariate logistic regression analyses were performed to identify predictors of mesh exposure complications. RESULTS: One hundred twenty-one patients with breast cancer had TVT surgery. Two hundred ninety-seven patients without cancer had TVT surgery during the same period. Baseline characteristics across all groups were similar. Twenty-nine patients (6.9%) experienced mesh exposure. This occurred at a higher rate in our cancer (15.7%) versus the noncancer population (3.4%). Women with breast cancer taking HS therapy had a higher rate of mesh exposure complications compared with those not taking HS therapy (25.0% versus 6.6%; P = 0.005). The highest rate of mesh exposure complications occurred in the cohort taking estrogen receptor modulators, selective estrogen receptor modulator (10/36 [27.8%]) versus aromatase inhibitors (5/24 [20.8%]) versus no HS therapy (4/61 [6.6%]; P = 0.014). On multivariate analysis, HS therapy use (odds ratio, 1.57; P = 0.007) and diabetes mellitus (odds ratio, 4.53; P = 0.018) were associated with increased TVT-related complications. CONCLUSION: Women with breast cancer had a higher rate of mesh exposure complications from TVT surgery compared with women without cancer, particularly those taking antiestrogenic therapy.
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Neoplasias de la Mama , Supervivientes de Cáncer , Cabestrillo Suburetral , Humanos , Femenino , Estudios Retrospectivos , Neoplasias de la Mama/tratamiento farmacológico , Mallas Quirúrgicas/efectos adversos , Cabestrillo Suburetral/efectos adversos , Moduladores de los Receptores de Estrógeno/efectos adversosRESUMEN
PURPOSE: The optimal adjuvant therapy (antiestrogen therapy [ET] + radiation therapy or ET alone, or in some reports radiation therapy alone) in older women with early-stage breast cancer has been highly debated. However, granular details on the role of insurance in the out-of-pocket cost for patients receiving ET with or without radiation therapy are lacking. This project disaggregates out-of-pocket costs by insurance plans to increase treatment cost transparency. METHODS AND MATERIALS: Several radiation therapy schedules are accepted standards as per the National Comprehensive Cancer Network guidelines. For our financial estimate model, we used the 5-fraction and 15-fraction radiation therapy and ET prescribed over a 5-year duration. The total aggregate out-of-pocket costs were determined from the sum of treatment costs, deductibles, and copays/coinsurance based on Medicaid, Original Medicare, Medigap Plan G, and Medicare Part D Rx plans. The model assumes a Medicare- and/or Medicaid-eligible patient ≥70 years of age with node-negative, early-stage estrogen-receptor-positive breast cancer. Patient out-of-pocket costs were estimated from publicly available insurance data from plan-specific benefit coverage materials using a 5-year time horizon. RESULTS: Original Medicare beneficiaries face a total out-of-pocket treatment charge of $2738.52 for ET alone, $2221.26 for 5-fraction radiation therapy alone, $2573.92 for 15-fraction radiation therapy alone, $3361.26 for combined ET+ 5-fraction radiation therapy, and $3713.92 for combined ET + 15-fraction radiation therapy. Medigap Plan G beneficiaries have an out-of-pocket charge of $1130.00 with radiation therapy alone and face an out-of-pocket of $2270.00 for ET alone and combined ET+ radiation therapy. For Medicaid beneficiaries, all treatments approved by Medicaid are covered without limit, resulting in no out-of-pocket expense for either adjuvant treatment option. CONCLUSIONS: This model (based on actual cost estimates per insurance plan rather than claims data), by estimating expenses within Medicare and Medicaid plans, provides a level of transparency to patient cost. With knowledge of the costs borne by patients themselves, treatment decisions informed by patients' individual priorities and preferences may be further enhanced.
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Neoplasias de la Mama , Gastos en Salud , Mastectomía Segmentaria , Medicaid , Medicare , Humanos , Neoplasias de la Mama/radioterapia , Neoplasias de la Mama/patología , Neoplasias de la Mama/economía , Neoplasias de la Mama/cirugía , Neoplasias de la Mama/terapia , Femenino , Estados Unidos , Medicaid/economía , Gastos en Salud/estadística & datos numéricos , Mastectomía Segmentaria/economía , Medicare/economía , Moduladores de los Receptores de Estrógeno/uso terapéutico , Moduladores de los Receptores de Estrógeno/economía , Radioterapia Adyuvante/economía , Deducibles y Coseguros/economía , Anciano , Modelos Económicos , Quimioterapia Adyuvante/economía , Medicare Part D/economía , Fraccionamiento de la Dosis de RadiaciónRESUMEN
Immune checkpoints regulate the immune system response. Recent studies suggest that flavonoids, known as phytoestrogens, may inhibit the PD-1/PD-L1 axis. We explored the potential of estrogens and 17 Selective Estrogen Receptor Modulators (SERMs) as inhibiting ligands for immune checkpoint proteins (CTLA-4, PD-L1, PD-1, and CD80). Our docking studies revealed strong binding energy values for quinestrol, quercetin, and bazedoxifene, indicating their potential to inhibit PD-1 and CTLA-4. Quercetin and bazedoxifene, known to modulate EGFR and IL-6R alongside estrogen receptors, can influence the immune checkpoint functionality. We discuss the impact of SERMs on PD-1 and CTLA-4, suggesting that these SERMs could have therapeutic effects through immune checkpoint inhibition. This study highlights the potential of SERMs as inhibitory ligands for immune checkpoint proteins, emphasizing the importance of considering PD-1 and CTLA-4 inhibition when evaluating SERMs as therapeutic agents. Our findings open new avenues for cancer immunotherapy by exploring the interaction between various SERMs and immune checkpoint pathways.
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Proteínas de Punto de Control Inmunitario , Neoplasias , Humanos , Antígeno CTLA-4 , Antígeno B7-H1 , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Receptor de Muerte Celular Programada 1 , Moduladores de los Receptores de Estrógeno , Quercetina , Inmunoterapia , Neoplasias/terapiaRESUMEN
All three possible sulfamate derivatives of the selective estrogen receptor modulator Raloxifene (bis-sulfamate 7 and two mono-sulfamates 8-9) were synthesized and evaluated as inhibitors of the clinical drug target steroid sulfatase (STS), both in cell-free and in cell-based assays, and also as estrogen receptor (ER) modulators. Bis-sulfamate 7 was the most potent STS inhibitor with an IC50 of 12.2 nM in a whole JEG3 cell-based assay, with the two mono-sulfamates significantly weaker. The estrogen receptor-modulating activities of 7-9 showed generally lower affinities compared to Raloxifene HCl, diethylstilbestrol and other known ligands, with mono-sulfamate 8 being the best ligand (Ki of 1.5 nM) for ERα binding, although 7 had a Ki of 13 nM and both showed desirable antagonist activity. The antiproliferative activities of the sulfamate derivatives against the T-47D breast cancer cell line showed 7 as most potent (GI50 = 7.12 µM), comparable to that of Raloxifene. Compound 7 also showed good antiproliferative potency in the NCI-60 cell line panel with a GI50 of 1.34 µM against MDA-MB-231 breast cancer cells. Stability testing of 7-9 showed that bis-sulfamate 7 hydrolyzed by desulfamoylation at a surprisingly rapid rate, initially leading selectively to 8 and finally to Raloxifene 3 without formation of 9. The mechanisms of these hydrolysis reactions could be extensively rationalized. Conversion of Raloxifene (3) into its bis-sulfamate (7) thus produced a promising drug lead with nanomolar dual activity as an STS inhibitor and ERα antagonist, as a potential candidate for treatment of estrogen-dependent breast cancer.
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Neoplasias de la Mama , Clorhidrato de Raloxifeno , Ácidos Sulfónicos , Humanos , Femenino , Clorhidrato de Raloxifeno/farmacología , Receptor alfa de Estrógeno , Línea Celular Tumoral , Inhibidores Enzimáticos/química , Esteril-Sulfatasa , Neoplasias de la Mama/tratamiento farmacológico , Moduladores de los Receptores de EstrógenoRESUMEN
Endocrine resistance is a crucial challenge in estrogen receptor alpha (ERα)-positive breast cancer (BCa). Aberrant alteration in modulation of E2/ERα signaling pathway has emerged as the putative contributor for endocrine resistance in BCa. Herein, we demonstrate that MYSM1 as a deubiquitinase participates in modulating ERα action via histone and non-histone deubiquitination. MYSM1 is involved in maintenance of ERα stability via ERα deubiquitination. MYSM1 regulates relevant histone modifications on cis regulatory elements of ERα-regulated genes, facilitating chromatin decondensation. MYSM1 is highly expressed in clinical BCa samples. MYSM1 depletion attenuates BCa-derived cell growth in xenograft models and increases the sensitivity of antiestrogen agents in BCa cells. A virtual screen shows that the small molecule Imatinib could potentially interact with catalytic MPN domain of MYSM1 to inhibit BCa cell growth via MYSM1-ERα axis. These findings clarify the molecular mechanism of MYSM1 as an epigenetic modifier in regulation of ERα action and provide a potential therapeutic target for endocrine resistance in BCa.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/genética , Receptor alfa de Estrógeno/genética , Moduladores de los Receptores de Estrógeno/farmacología , Moduladores de los Receptores de Estrógeno/uso terapéutico , Histonas/metabolismo , Proliferación Celular , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica , Línea Celular Tumoral , Transactivadores/metabolismo , Proteasas Ubiquitina-Específicas/genética , Proteasas Ubiquitina-Específicas/metabolismoRESUMEN
The safety profile of hormone replacement therapy (HRT) on breast is still controversial. Tibolone is an option of treatment for climacteric syndrome of postmenopausal women. Its risk profile on breast is debated. This is an updated narrative review focusing on the impact of tibolone on breast. Particularly, we will report data from major preclinical and clinical studies regarding the effects of the use of this compound on breast tissue and breast density. Moreover, we will analyze and discuss the most relevant findings of the principal studies evaluating the relationship between tibolone and breast cancer risk. Our purpose is making all clinicians who are particularly involved in women's health more aware of the effects of this compound on breast and, thus, more experienced in the management of menopausal symptoms with this drug. According to the available literature, tibolone seems to be characterized by an interesting safety profile on breast tissue.
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Neoplasias de la Mama , Moduladores de los Receptores de Estrógeno , Femenino , Humanos , Moduladores de los Receptores de Estrógeno/efectos adversos , Norpregnenos/efectos adversos , Terapia de Reemplazo de Hormonas/efectos adversos , Neoplasias de la Mama/inducido químicamente , Neoplasias de la Mama/tratamiento farmacológicoRESUMEN
Traumatic brain injury (TBI) is a pathology of great social impact, affecting millions of people worldwide. Despite the scientific advances to improve the management of TBI in recent years, we still do not have a specific treatment that controls the inflammatory process after mechanical trauma. The discovery and implementation of new treatments is a long and expensive process, making the repurpose of approved drugs for other pathologies a clinical interest. Tibolone is a drug in use for the treatment of symptoms associated with menopause and has been shown to have a broad spectrum of actions by regulating estrogen, androgen and progesterone receptors, whose activation exerts potent anti-inflammatory and antioxidant effects. In the present study, we aimed to investigate the therapeutic potential of the tibolone metabolites 3α-Hydroxytibolone, 3ß-Hydroxytibolone, and Δ4-Tibolone as a possible therapy in TBI using network pharmacology and network topology analysis. Our results demonstrate that the estrogenic component mediated by the α and ß metabolites can regulate synaptic transmission and cell metabolism, while the Δ metabolite may be involved in modulating the post-TBI inflammatory process. We identified several molecular targets, including KDR, ESR2, AR, NR3C1, PPARD, and PPARA, which are known to play critical roles in the pathogenesis of TBI. Tibolone metabolites were predicted to regulate the expression of key genes involved in oxidative stress, inflammation, and apoptosis. Overall, the repurposing of tibolone as a neuroprotective treatment for TBI holds promise for future clinical trials. However, further studies are needed to confirm its efficacy and safety in TBI patients.
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Lesiones Traumáticas del Encéfalo , Farmacología en Red , Femenino , Humanos , Estrógenos/metabolismo , Moduladores de los Receptores de Estrógeno/farmacología , Lesiones Traumáticas del Encéfalo/tratamiento farmacológicoRESUMEN
Heterocyclic derivatives of steroid hormones are potent anticancer agents, which are used in the chemotherapy of breast and prostate cancers. Here, we describe a novel series of androstenes, D-modified with imidazole-annulated pendants, with significant anticancer activity. Novel C17-linked imidazole-annulated heterocyclic derivatives of dehydropregnenolone acetate were synthesized by the cyclocondensation with amidines using 3ß-acetoxy-21-bromopregna-5,16-dien-20-one as the substrate. The antiproliferative potency of all the synthesized compounds was evaluated against human prostate (22Rv1) and human breast (MCF7) cancer cell lines and cytochromes P450. The lead compound, imidazo[1,2-a]pyridine derivative 3h, was revealed to be a promising candidate for future anticancer drug design, particularly against ERα-positive breast cancer. Lead compound 3h was found to be selective against MCF7 cells with IC50 of 0.1 µM and to act as both a potent selective agent blocking estrogen receptor α, which is involved in the stimulation of breast cancer growth, and an effective apoptosis inducer. The potential ability of compound 3h to bind to ERα was studded using molecular docking and molecular dynamics simulation. The selectivity analysis showed that lead steroid 3h produces no effects on cytochromes P450 CYP17A1, CYP7A1, and CYP21A2.
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Antineoplásicos , Neoplasias de la Mama , Masculino , Humanos , Receptor alfa de Estrógeno , Moduladores de los Receptores de Estrógeno/farmacología , Simulación del Acoplamiento Molecular , Antineoplásicos/farmacología , Antineoplásicos/química , Esteroides/farmacología , Esteroides/química , Imidazoles/farmacología , Antagonistas de Estrógenos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Citocromos/farmacología , Proliferación Celular , Relación Estructura-Actividad , Ensayos de Selección de Medicamentos Antitumorales , Línea Celular Tumoral , Estructura MolecularRESUMEN
Adjuvant endocrine therapy (AET) is the treatment of choice for early-stage estrogen receptor alpha (ERα)-positive breast cancer (BC). However, almost 40% of tamoxifen-treated cases display no response or a partial response to AET, thus increasing the need for new treatment options and strong predictors of the therapeutic response of patients at high risk of relapse. In addition to ERα, BC research has focused on ERß1 and ERß2 (isoforms of ERß), the second ER isotype. At present, the impact of ERß isoforms on ERα-positive BC prognosis and treatment remains elusive. In the present study, we established clones of MCF7 cells constitutively expressing human ERß1 or ERß2 and investigated their role in the response of MCF7 cells to antiestrogens [4-hydroxytamoxifen (OHΤ) and fulvestrant (ICI182,780)] and retinoids [all-trans retinoic acid (ATRA)]. We show that, compared to MCF7 cells, MCF7-ERß1 and MCF7-ERß2 cells were sensitized and desensitized, respectively, to the antiproliferative effect of the antiestrogens, ATRA and their combination and to the cytocidal effect of the combination of OHT and ATRA. Analysis of the global transcriptional changes upon OHT-ATRA combinatorial treatment revealed uniquely regulated genes associated with anticancer effects in MCF7-ERß1 cells and cancer-promoting effects in MCF7-ERß2 cells. Our data are favorable to ERß1 being a marker of responsiveness and ERß2 being a marker of resistance of MCF7 cells to antiestrogens alone and in combination with ATRA.
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Neoplasias de la Mama , Resistencia a Antineoplásicos , Receptor beta de Estrógeno , Femenino , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Resistencia a Antineoplásicos/genética , Antagonistas de Estrógenos/uso terapéutico , Receptor alfa de Estrógeno/genética , Receptor beta de Estrógeno/genética , Receptor beta de Estrógeno/metabolismo , Moduladores de los Receptores de Estrógeno/uso terapéutico , Fulvestrant/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Isoformas de Proteínas , Tamoxifeno/uso terapéutico , Tretinoina/uso terapéuticoRESUMEN
Objectives: The aim of this study was to evaluate the impact of acupuncture on hot flashes in breast cancer patients taking tamoxifen as an adjuvant antiestrogen therapy in Korea. Design: This trial was a randomized, no-treatment-controlled, single-blind, multi-center trial. Participants were randomized 1:1 into the acupuncture group or into the no-treatment control group. Location: This trial was conducted at Daegu Catholic University Hospital and Daegu Haany University Korean Medicine Hospital in Daegu, Republic of Korea. Participants: Patients with moderate to severe symptoms of hot flashes while receiving adjuvant antiestrogen therapy using tamoxifen after surgery for breast cancer were included. Interventions: In the acupuncture group, acupuncture was performed three times a week for 4 consecutive weeks at five predetermined points. The control group received no treatment during the study period. Study Outcome Measures: As a primary outcome, the severity of hot flashes was measured on the visual analogue scale (VAS) and total hot flash score. In addition, the quality of life (QoL) of participants was assessed as a secondary outcome. Results: A total of 30 patients were included in this study, 15 each in the acupuncture group and the control group. The participants in the acupuncture group significantly decreased the severity of hot flashes evaluated with both VAS and total hot flash scores compared with participants in the control group. Also, the acupuncture group showed improved score of a global health status/QoL scale and functional scales assessed with the European Organisation for Research and Treatment of Cancer QoL questionnaire-core questionnaire, compared with those in the control group. This trend was maintained 4 weeks after acupuncture treatment. No adverse events have been reported in this study. Conclusions: Acupuncture was effective and safe in improving hot flashes in Korean breast cancer patients receiving adjuvant antiestrogen therapy with tamoxifen, and it improved the QoL. Clinical Trial Registration: KCT0007829.
Asunto(s)
Terapia por Acupuntura , Neoplasias de la Mama , Humanos , Femenino , Tamoxifeno/efectos adversos , Neoplasias de la Mama/complicaciones , Neoplasias de la Mama/tratamiento farmacológico , Sofocos/inducido químicamente , Sofocos/terapia , Calidad de Vida , Moduladores de los Receptores de Estrógeno/uso terapéutico , Método Simple Ciego , Antagonistas de Estrógenos/efectos adversosRESUMEN
BACKGROUND: Lung cancer death remains the highest among all malignancies. Gender differences show women have an increased cancer incidence while men have worse outcomes. These observations identified that some lung carcinomas express estrogen receptors (ER). This is a promising target as antiestrogen drugs can reduce tumors and improve survival. However, there is a limited understanding of ER distribution and its clinical significance to properly design antiestrogen drug clinical trials. Thus, we comprehensively analyzed ERα and ERß expression patterns by gender, cancer cell type, and receptor location in lung cancer. METHODS: We conducted a systematic review using the PubMed database from all-time through October 2022, using MeSH terms with the keywords "lung cancer," "estrogen receptor," and "immunohistochemistry." We identified 120 studies with 21 reports being evaluated based on our inclusion criteria. RESULTS: We examined 4874 lung cancers from 5011 patients. ERß is the predominant form of ER expressed, mainly found in the nucleus. The ERß positivity rate is 51.5% in males versus 55.5% in females and was not statistically different. In contrast, ERα is predominately extranuclear in location, and ERα expression varies by gender. Males had a positivity rate of 31% versus 26.6% in females, which is statistically different. ERα is associated with a worse prognosis in some studies, while it had no effect in others. Overall, ERß was associated with a better prognosis. CONCLUSION: We characterized ER expression patterns in 4874 lung cancers. Over 50% expressed ERß with equal rates in both sexes and was associated with a better prognosis. ERα expression was slightly higher in males (31%) than females (26.6%) and was associated with a poor prognosis. Our findings suggest estrogen signaling may be a promising drug target in lung cancer.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Masculino , Humanos , Femenino , Receptores de Estrógenos , Carcinoma de Pulmón de Células no Pequeñas/patología , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/metabolismo , Neoplasias Pulmonares/patología , Relevancia Clínica , Moduladores de los Receptores de EstrógenoRESUMEN
Antiestrogens (AEs) are used to treat all stages of estrogen receptor (ER)-positive breast cancer. Selective estrogen receptor modulators such as tamoxifen have tissue-specific partial agonist activity, while selective estrogen receptor downregulators such as fulvestrant (ICI182,780) display a more complete antiestrogenic profile. We have previously observed that fulvestrant-induced ERα SUMOylation contributes to transcriptional suppression, but whether this effect is seen with other AEs and is specific to ERα is unclear. Here we show that several AEs induce SUMOylation of ERα, but not ERß, at different levels. Swapping domains between ERα and ERß indicates that the ERα identity of the ligand-binding domain helices 3 and 4 (H3-H4 region), which contribute to the static part of the activation function-2 (AF-2) cofactor binding groove, is sufficient to confer fulvestrant-induced SUMOylation to ERß. This region does not contain lysine residues unique to ERα, suggesting that ERα-specific residues in H3-H4 determine the capacity of the AE-bound ERα ligand-binding domain to recruit the SUMOylation machinery. We also show that the SUMO E3 ligase protein inhibitor of activated STAT 1 increases SUMOylation of ERα and of ERß containing the H3-H4 region of ERα, but not of ERß. Together, these results shed new light on the molecular basis for the differential capacity of selective estrogen receptor modulators and selective estrogen receptor downregulators to suppress transcription by ERα.
Asunto(s)
Neoplasias de la Mama , Receptor alfa de Estrógeno , Humanos , Femenino , Receptor alfa de Estrógeno/metabolismo , Moduladores de los Receptores de Estrógeno/farmacología , Receptores de Estrógenos/metabolismo , Fulvestrant/farmacología , Furilfuramida , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Sumoilación , Ligandos , Antagonistas de Estrógenos/farmacología , Tamoxifeno/farmacología , Neoplasias de la Mama/metabolismo , Receptor beta de Estrógeno/genética , Receptor beta de Estrógeno/metabolismo , Estradiol/farmacologíaRESUMEN
The epidermal growth factor receptor (EGFR) is commonly upregulated in multiple cancer types, including breast cancer. In the present study, evidence is provided in support of the premise that upregulation of the EGFR/MEK1/MAPK1/2 signaling axis during antiestrogen treatment facilitates the escape of breast cancer cells from BimELdependent apoptosis, conferring resistance to therapy. This conclusion is based on the findings that ectopic BimEL cDNA overexpression and confocal imaging studies confirm the proapoptotic role of BimEL in ERα expressing breast cancer cells and that upregulated EGFR/MEK1/MAPK1/2 signaling blocks BimEL proapoptotic action in an antiestrogenresistant breast cancer cell model. In addition, the present study identified a prosurvival role for autophagy in antiestrogen resistance while EGFR inhibitor studies demonstrated that a significant percentage of antiestrogenresistant breast cancer cells survive EGFR targeting by prosurvival autophagy. These preclinical studies establish the possibility that targeting both the MEK1/MAPK1/2 signaling axis and prosurvival autophagy may be required to eradicate breast cancer cell survival and prevent the development of antiestrogen resistance following hormone treatments. The present study uniquely identified EGFR upregulation as one of the mechanisms breast cancer cells utilize to evade the cytotoxic effects of antiestrogens mediated through BimELdependent apoptosis.
Asunto(s)
Apoptosis , Neoplasias de la Mama , Resistencia a Antineoplásicos , Moduladores de los Receptores de Estrógeno , Femenino , Humanos , Apoptosis/efectos de los fármacos , Proteína 11 Similar a Bcl2/efectos de los fármacos , Proteína 11 Similar a Bcl2/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Resistencia a Antineoplásicos/fisiología , Receptores ErbB/genética , Receptores ErbB/metabolismo , Moduladores de los Receptores de Estrógeno/farmacología , Moduladores de los Receptores de Estrógeno/uso terapéutico , Proteína Quinasa 1 Activada por Mitógenos/genética , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Regulación hacia Arriba , Transducción de SeñalRESUMEN
Antiestrogen medication is the only chemoprevention currently available for women at a high risk of developing breast cancer; however, antiestrogen therapy requires years to achieve efficacy and has adverse side effects. Therefore, it is important to develop an efficacious chemoprevention strategy that requires only a short course of treatment. PIK3CA is commonly activated in breast atypical hyperplasia, the known precancerous precursor of breast cancer. Targeting PI3K signaling in these precancerous lesions may offer a new strategy for chemoprevention. Here, we first established a mouse model that mimics the progression from precancerous lesions to breast cancer. Next, we demonstrated that a short-course prophylactic treatment with the clinically approved PI3K inhibitor alpelisib slowed early lesion expansion and prevented cancer formation in this model. Furthermore, we showed that alpelisib suppressed ex vivo expansion of patient-derived atypical hyperplasia. Together, these data indicate that the progression of precancerous breast lesions heavily depends on the PI3K signaling, and that prophylactic targeting of PI3K activity can prevent breast cancer. PREVENTION RELEVANCE: PI3K protein is abnormally high in breast precancerous lesions. This preclinical study demonstrates that the FDA-approved anti-PI3K inhibitor alpelisib can prevent breast cancer and thus warrant future clinical trials in high-risk women.