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1.
Cell Transplant ; 30: 963689721991477, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33522308

RESUMEN

TRANSLATIONAL RELEVANCE: No prophylactic treatments for COVID-19 have been clearly proven and found. In this pandemic context, cancer patients constitute a particularly fragile population that would benefit the best from such treatments, a present unmet need. TMPRSS2 is essential for COVID-19 replication cycle and it is under androgen control. Estrogen and androgen receptor dependent cues converge on TMPRSS2 regulation through different mechanisms of action that can be blocked by the use of hormonal therapies. We believe that there is enough body of evidence to foresee a prophylactic use of hormonal therapies against COVID-19 and this hypothesis can be easily tested on cohorts of breast and prostate cancer patients who follow those regimens. In case of pandemic, if the protective effect of hormonal therapies will be proven on cancer patients, the use of specific hormonal therapies could be extended to other oncological groups and to healthy individuals to decrease the overall risk of infection by SARS-CoV-2.Given the COVID-19 coronavirus emergency, a special focus is needed on the impact of this rapidly spreading viral infection on cancer patients. Androgen receptor (AR) signaling in the transmembrane protease serine 2 (TMPRSS2) regulation is emerging as an important determinant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) susceptibility. In our study, we analyzed AR and TMPRSS2 expression in 17,352 normal and 9,556 cancer tissues from public repositories and stratified data according to sex and age. The emerging picture is that some patient groups may be particularly susceptible to SARS-CoV-2 infection and may benefit from antiandrogen- or tamoxifen-based therapies. These findings are relevant to choose proper treatments in order to protect cancer patients from concomitant SARS-CoV-2 contagion and related symptoms and put forward the idea that hormonal therapies could be used as prophylactic agents against COVID-19.


Asunto(s)
Antagonistas de Receptores Androgénicos/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/complicaciones , Antagonistas de Estrógenos/uso terapéutico , Neoplasias de la Próstata/complicaciones , Tamoxifeno/uso terapéutico , Antagonistas de Receptores Androgénicos/farmacología , Antineoplásicos Hormonales/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , /metabolismo , Descubrimiento de Drogas , Antagonistas de Estrógenos/farmacología , Femenino , Humanos , Masculino , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/análisis , Receptores Androgénicos/metabolismo , Serina Endopeptidasas/análisis , Serina Endopeptidasas/metabolismo , Transducción de Señal/efectos de los fármacos , Tamoxifeno/farmacología
2.
Int J Mol Sci ; 22(2)2021 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-33451133

RESUMEN

Breast cancer (BC) is the most common cancer among women worldwide. More than 70% of BC cases express estrogen receptor alpha (ERα), a central transcription factor that stimulates the proliferation of breast cancer cells, usually in the presence of estrogen. While most cases of ER-positive BC initially respond to antiestrogen therapies, a high percentage of cases develop resistance to treatment over time. The recent discovery of mutated forms of ERα that result in constitutively active forms of the receptor in the metastatic-resistance stage of BC has provided a strong rationale for the development of new antiestrogens. These molecules targeting clinically relevant ERα mutants and a combination with other pharmacological inhibitors of specific pathways may constitute alternative treatments to improve clinical practice in the fight against metastatic-resistant ER-positive BC. In this review, we summarize the latest advances regarding the particular involvement of point mutations of ERα in endocrine resistance. We also discuss the involvement of synonymous ERα mutations with respect to co-translational folding of the receptor and ribosome biogenesis in breast carcinogenesis.


Asunto(s)
Biomarcadores de Tumor , Neoplasias de la Mama/etiología , Neoplasias de la Mama/metabolismo , Mutación , Receptores Estrogénicos/genética , Animales , Antineoplásicos Hormonales/farmacología , Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Antagonistas de Estrógenos/farmacología , Antagonistas de Estrógenos/uso terapéutico , Receptor alfa de Estrógeno/antagonistas & inhibidores , Receptor alfa de Estrógeno/química , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Estrógenos/farmacología , Estrógenos/uso terapéutico , Femenino , Humanos , Terapia Molecular Dirigida , Mutación Missense , Receptores Estrogénicos/antagonistas & inhibidores , Receptores Estrogénicos/química , Receptores Estrogénicos/metabolismo , Mutación Silenciosa , Relación Estructura-Actividad
3.
Molecules ; 26(1)2021 Jan 04.
Artículo en Inglés | MEDLINE | ID: mdl-33406699

RESUMEN

Conventional chemotherapies used for breast cancer (BC) treatment are non-selective, attacking both healthy and cancerous cells. Therefore, new technologies that enhance drug efficacy and ameliorate the off-target toxic effects exhibited by currently used anticancer drugs are urgently needed. Here we report the design and synthesis of novel mesoporous silica nanoparticles (MSNs) equipped with the hormonal drug tamoxifen (TAM) to facilitate guidance towards estrogen receptors (ERs) which are upregulated in breast tumours. TAM is linked to the MSNs using a poly-ʟ-histidine (PLH) polymer as a pH-sensitive gatekeeper, to ensure efficient delivery of encapsulated materials within the pores. XRD, HR-TEM, DLS, SEM, FT-IR and BET techniques were used to confirm the successful fabrication of MSNs. The MSNs have a high surface area (>1000 m2/g); and a mean particle size of 150 nm, which is an appropriate size to allow the penetration of premature blood vessels surrounding breast tumours. Successful surface functionalization was supported by FT-IR, XPS and TGA techniques, with a grafting ratio of approximately 29%. The outcomes of this preliminary work could be used as practical building blocks towards future formulations.


Asunto(s)
Antineoplásicos Hormonales/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos , Nanopartículas/administración & dosificación , Dióxido de Silicio/química , Tamoxifeno/farmacología , Antineoplásicos Hormonales/química , Composición de Medicamentos , Diseño de Fármacos , Descubrimiento de Drogas , Liberación de Fármacos , Femenino , Humanos , Nanopartículas/química , Porosidad , Tamoxifeno/química
4.
Cancer Sci ; 112(4): 1603-1613, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33453094

RESUMEN

Breast cancer is the leading cause of cancer death in women. Hormone-receptor-positive breast cancer (HR + BC) is the most common pathological type of breast cancer, of which the main treatment method is endocrine therapy. Unfortunately, primary or acquired drug resistance greatly limits its efficacy. In recent years, the newly launched CDK4/6 inhibitors could effectively reverse endocrine resistance in breast cancer. However, considering their expensive price and side effects, it is particularly important to find out effective biomarkers and screen sensitive patients. Here, we found through bioinformatics analysis that high mobility group box 1 (HMGB1) expression increased in endocrine-resistant HR + BC. In clinical specimens, the higher expression of HMGB1 was associated with shorter progression-free survival (PFS) for HR + BC patients with endocrine therapy after surgery. For endocrine-resistant breast cancer, compared with HMGB1-negative patients, HMGB1-positive patients who received CDK4/6 inhibitors treatment benefited more in PFS. Moreover, we demonstrated that HMGB1 promoted tamoxifen resistance by combining with the Toll-like receptor 4 (TLR4) and activating nuclear factor kappa B (NF-κB) pathway. CDK4/6 inhibitors could downregulate the expression of HMGB1 and suppress the TLR4-NF-κB pathway, and in turn reverse tamoxifen resistance. These results illuminated the critical role of HMGB1 in the process of tamoxifen resistance, explained the mechanism of CDK4/6 inhibitors reversing tamoxifen resistance, and suggested the feasibility of HMGB1 as a potential biomarker for screening sensitive patients receiving CDK4/6 inhibitors.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Resistencia a Antineoplásicos/fisiología , Proteína HMGB1/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Tamoxifeno/farmacología , Antineoplásicos Hormonales/farmacología , Mama/efectos de los fármacos , Mama/metabolismo , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Humanos , Células MCF-7 , FN-kappa B/metabolismo , Supervivencia sin Progresión , Receptor ErbB-2/metabolismo , Receptores Estrogénicos/metabolismo , Transducción de Señal/efectos de los fármacos
5.
Nat Commun ; 11(1): 5513, 2020 11 02.
Artículo en Inglés | MEDLINE | ID: mdl-33139730

RESUMEN

Cyclin D1 is one of the most important oncoproteins that drives cancer cell proliferation and associates with tamoxifen resistance in breast cancer. Here, we identify a lncRNA, DILA1, which interacts with Cyclin D1 and is overexpressed in tamoxifen-resistant breast cancer cells. Mechanistically, DILA1 inhibits the phosphorylation of Cyclin D1 at Thr286 by directly interacting with Thr286 and blocking its subsequent degradation, leading to overexpressed Cyclin D1 protein in breast cancer. Knocking down DILA1 decreases Cyclin D1 protein expression, inhibits cancer cell growth and restores tamoxifen sensitivity both in vitro and in vivo. High expression of DILA1 is associated with overexpressed Cyclin D1 protein and poor prognosis in breast cancer patients who received tamoxifen treatment. This study shows the previously unappreciated importance of post-translational dysregulation of Cyclin D1 contributing to tamoxifen resistance in breast cancer. Moreover, it reveals the novel mechanism of DILA1 in regulating Cyclin D1 protein stability and suggests DILA1 is a specific therapeutic target to downregulate Cyclin D1 protein and reverse tamoxifen resistance in treating breast cancer.


Asunto(s)
Antineoplásicos Hormonales/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Ciclina D1/genética , ARN Largo no Codificante/metabolismo , Tamoxifeno/farmacología , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/genética , Supervivencia sin Enfermedad , Resistencia a Antineoplásicos/genética , Femenino , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Persona de Mediana Edad , Pronóstico , Procesamiento Proteico-Postraduccional/genética , Estabilidad Proteica , Proteolisis , ARN Largo no Codificante/genética , Tamoxifeno/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto , Adulto Joven
6.
Nucleic Acids Res ; 48(19): 10768-10784, 2020 11 04.
Artículo en Inglés | MEDLINE | ID: mdl-32986841

RESUMEN

Estrogen receptor alpha (ERα) signaling pathway is essential for ERα-positive breast cancer progression and endocrine therapy resistance. Bromodomain PHD Finger Transcription Factor (BPTF) associated protein of 18kDa (BAP18) has been recognized as a crucial H3K4me3 reader. However, the whole genomic occupation of BAP18 and its biological function in breast cancer is still elusive. Here, we found that higher expression of BAP18 in ERα-positive breast cancer is positively correlated with poor prognosis. ChIP-seq analysis further demonstrated that the half estrogen response elements (EREs) and the CCCTC binding factor (CTCF) binding sites are the significant enrichment sites found in estrogen-induced BAP18 binding sites. Also, we provide the evidence to demonstrate that BAP18 as a novel co-activator of ERα is required for the recruitment of COMPASS-like core subunits to the cis-regulatory element of ERα target genes in breast cancer cells. BAP18 is recruited to the promoter regions of estrogen-induced genes, accompanied with the enrichment of the lysine 4-trimethylated histone H3 tail (H3K4me3) in the presence of E2. Furthermore, BAP18 promotes cell growth and associates the sensitivity of antiestrogen in ERα-positive breast cancer. Our data suggest that BAP18 facilitates the association between ERα and COMPASS-like core subunits, which might be an essential epigenetic therapeutic target for breast cancer.


Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Proteínas de Unión al ADN/genética , Resistencia a Antineoplásicos , Receptor alfa de Estrógeno/genética , Código de Histonas , Animales , Antineoplásicos Hormonales/farmacología , Antineoplásicos Hormonales/uso terapéutico , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proteínas de Unión al ADN/metabolismo , Moduladores de los Receptores de Estrógeno/farmacología , Moduladores de los Receptores de Estrógeno/uso terapéutico , Receptor alfa de Estrógeno/antagonistas & inhibidores , Receptor alfa de Estrógeno/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Humanos , Células MCF-7 , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/genética , Neoplasias Mamarias Experimentales/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Elementos de Respuesta
7.
Breast Cancer Res ; 22(1): 80, 2020 07 29.
Artículo en Inglés | MEDLINE | ID: mdl-32727562

RESUMEN

BACKGROUND: The estrogen receptor (ER)-positive breast cancer represents over 80% of all breast cancer cases. Even though adjuvant hormone therapy with tamoxifen (TMX) is saving lives of patients with ER-positive breast cancer, the acquired resistance to TMX anti-estrogen therapy is the main hurdle for successful TMX therapy. Here we address the mechanism for TMX resistance and explore the ways to eradicate TMX-resistant breast cancer in both in vitro and ex vivo experiments. EXPERIMENTAL DESIGN: To identify compounds able to overcome TMX resistance, we used short-term and long-term viability assays in cancer cells in vitro and in patient samples in 3D ex vivo, analysis of gene expression profiles and cell line pharmacology database, shRNA screen, CRISPR-Cas9 genome editing, real-time PCR, immunofluorescent analysis, western blot, measurement of oxidative stress using flow cytometry, and thioredoxin reductase 1 enzymatic activity. RESULTS: Here, for the first time, we provide an ample evidence that a high level of the detoxifying enzyme SULT1A1 confers resistance to TMX therapy in both in vitro and ex vivo models and correlates with TMX resistance in metastatic samples in relapsed patients. Based on the data from different approaches, we identified three anticancer compounds, RITA (Reactivation of p53 and Induction of Tumor cell Apoptosis), aminoflavone (AF), and oncrasin-1 (ONC-1), whose tumor cell inhibition activity is dependent on SULT1A1. We discovered thioredoxin reductase 1 (TrxR1, encoded by TXNRD1) as a target of bio-activated RITA, AF, and ONC-1. SULT1A1 depletion prevented the inhibition of TrxR1, induction of oxidative stress, DNA damage signaling, and apoptosis triggered by the compounds. Notably, RITA efficiently suppressed TMX-unresponsive patient-derived breast cancer cells ex vivo. CONCLUSION: We have identified a mechanism of resistance to TMX via hyperactivated SULT1A1, which renders selective vulnerability to anticancer compounds RITA, AF, and ONC-1, and provide a rationale for a new combination therapy to overcome TMX resistance in breast cancer patients. Our novel findings may provide a strategy to circumvent TMX resistance and suggest that this approach could be developed further for the benefit of relapsed breast cancer patients.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Bibliotecas de Moléculas Pequeñas/farmacología , Tamoxifeno/farmacología , Antineoplásicos Hormonales/química , Antineoplásicos Hormonales/farmacología , Apoptosis , Arilsulfotransferasa/genética , Arilsulfotransferasa/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos , Femenino , Humanos , Tamoxifeno/química , Células Tumorales Cultivadas
8.
Toxicol Appl Pharmacol ; 401: 115118, 2020 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-32619553

RESUMEN

Glucocorticoid receptor (GR) modulates extensive biological and pathological processes including tumor progression through diverse mechanisms. The regulatory effects of dexamethasone (DEX), a synthetic glucocorticoid, as well as its interaction with GR have been recognized beyond hematologic cancers. In the present study, we investigated the anti-cancer efficacy of DEX and the correlation with GR in pancreatic cancer, a most aggressive malignancy threatening human health. The differential levels of GR expression were examined in two human pancreatic cancer cell lines, PANC-1 and SW1990, as well as in xenografts and patient tumor tissues. DEX significantly inhibited colony formation, migration, and tumor growth of PANC-1 cells expressing abundant GR. The underlying mechanisms involved suppression of nuclear factor κB (NF-κB) phosphorylation and down-regulation of epithelial-to-mesenchymal transition (EMT), interleukin 6 (IL-6) and vascular endothelial growth factor (VEGF). The anti-cancer effects of DEX were partially reversed by GR silencing or combinational administration of GR antagonist, RU486. The dose-dependent efficacy of DEX in tumor growth inhibition was also demonstrated in a GR-positive patient-derived xenograft model along with safety in mice. DEX was less potent, however, in SW1990 cells with poor GR expression. Our findings suggest that DEX effectively inhibits pancreatic tumor growth partially through GR activation. The potential correlation between GR expression and anti-cancer efficacy of DEX may have some clinical implications.


Asunto(s)
Antineoplásicos Hormonales/uso terapéutico , Dexametasona/uso terapéutico , Neoplasias Pancreáticas/metabolismo , Receptores de Glucocorticoides/metabolismo , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Células A549 , Animales , Antineoplásicos Hormonales/farmacología , Dexametasona/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Glucocorticoides/farmacología , Glucocorticoides/uso terapéutico , Humanos , Células MCF-7 , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias Pancreáticas/tratamiento farmacológico , Carga Tumoral/fisiología
9.
Mol Cancer Ther ; 19(9): 1909-1921, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32546662

RESUMEN

Mitotane causes hypercholesterolemia in patients with adrenocortical carcinoma (ACC). We suppose that cholesterol increases within the tumor and can be used to activate proliferative pathways. In this study, we used statins to decrease intratumor cholesterol and investigated the effects on ACC growth related to estrogen receptor α (ERα) action at the nuclear and mitochondrial levels. We first used microarray to investigate mitotane effect on genes involved in cholesterol homeostasis and evaluated their relationship with patients' survival in ACC TCGA. We then blocked cholesterol synthesis with simvastatin and determined the effects on H295R cell proliferation, estradiol production, and ERα activity in vitro and in xenograft tumors. We found that mitotane increases intratumor cholesterol content and expression of genes involved in cholesterol homeostasis, among them INSIG, whose expression affects patients' survival. Treatment of H295R cells with simvastatin to block cholesterol synthesis decreased cellular cholesterol content, and this affected cell viability. Simvastatin reduced estradiol production and decreased nuclear and mitochondrial ERα function. A mitochondrial target of ERα, the respiratory complex IV (COXIV), was reduced after simvastatin treatment, which profoundly affected mitochondrial respiration activating apoptosis. Additionally, simvastatin reduced tumor volume and weight of grafted H295R cells, intratumor cholesterol content, Ki-67 and ERα, COXIV expression and activity and increase terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells. Collectively, these data demonstrate that a reduction in intratumor cholesterol content prevents estradiol production and inhibits mitochondrial respiratory chain-inducing apoptosis in ACC cells. Inhibition of mitochondrial respiration by simvastatin represents a novel strategy to counteract ACC growth.


Asunto(s)
Neoplasias de la Corteza Suprarrenal/tratamiento farmacológico , Carcinoma Corticosuprarrenal/tratamiento farmacológico , Antineoplásicos Hormonales/uso terapéutico , Colesterol/química , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Mitotano/uso terapéutico , Animales , Antineoplásicos Hormonales/farmacología , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Ratones , Mitotano/farmacología
12.
Nat Cell Biol ; 22(6): 701-715, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32424275

RESUMEN

Acquired therapy resistance is a major problem for anticancer treatment, yet the underlying molecular mechanisms remain unclear. Using an established breast cancer cellular model, we show that endocrine resistance is associated with enhanced phenotypic plasticity, indicated by a general downregulation of luminal/epithelial differentiation markers and upregulation of basal/mesenchymal invasive markers. Consistently, similar gene expression changes are found in clinical breast tumours and patient-derived xenograft samples that are resistant to endocrine therapies. Mechanistically, the differential interactions between oestrogen receptor α and other oncogenic transcription factors, exemplified by GATA3 and AP1, drive global enhancer gain/loss reprogramming, profoundly altering breast cancer transcriptional programs. Our functional studies in multiple culture and xenograft models reveal a coordinated role of GATA3 and AP1 in re-organizing enhancer landscapes and regulating cancer phenotypes. Collectively, our study suggests that differential high-order assemblies of transcription factors on enhancers trigger genome-wide enhancer reprogramming, resulting in transcriptional transitions that promote tumour phenotypic plasticity and therapy resistance.


Asunto(s)
Adaptación Fisiológica , Neoplasias de la Mama/tratamiento farmacológico , Reprogramación Celular , Resistencia a Antineoplásicos , Factor de Transcripción GATA3/metabolismo , Regulación Neoplásica de la Expresión Génica , Factor de Transcripción AP-1/metabolismo , Animales , Antineoplásicos Hormonales/farmacología , Apoptosis , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proliferación Celular , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Femenino , Factor de Transcripción GATA3/genética , Humanos , Ratones , Ratones Desnudos , Tamoxifeno/farmacología , Factor de Transcripción AP-1/genética , Activación Transcripcional , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
13.
J Steroid Biochem Mol Biol ; 201: 105698, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32404282

RESUMEN

Estrogen receptor (ER)α and the human epidermal growth factor receptor (HER) family are inversely expressed in ERα-positive cancer in association with resistance to hormonal therapy, but the mechanism underlying their relationship remains unknown. We analyzed the effect of HER family ligands on the expression of ER and the HER family in ERα-positive MCF-7 and T47D breast cancer cell lines in 3D spheroid culture. Here, we demonstrated for the first time that heregulin-1ß (HRG), a HER3 and HER4 ligand, most effectively regulated ER/HER family expression by decreasing ERα mRNA expression and increasing HER family mRNA expression. HRG treatment attenuated fulvestrant-mediated growth inhibition, and promoted the migration of MCF-7 cells. Moreover, HRG increased the CD44+/CD24- cell fraction and side population cells, both of which are recognized as prospective breast cancer stem cell markers. HRG activated both phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) and mitogen-activated protein kinase (MAPK) pathways. Inhibitors of these pathways reduced the growth of MCF-7 cells, but the addition of HRG has different effects on these pathways. HRG blocked the inhibitory effect of mTOR inhibitors, such as rapamycin and everolimus, on cell growth but not that of a PI3K inhibitor. Furthermore, HRG slightly decreased the inhibitory effect of an AKT inhibitor on cell growth. In contrast, HRG enhanced the MEK inhibitor-induced inhibition of cell growth. These findings suggest that HRG-stimulated signaling pathways allow ERα-positive breast cancer cells to escape from growth inhibition caused by everolimus, via MAPK signaling and/or other signaling pathways. Everolimus improves progression-free survival in combination with exemestane as second-line therapy for metastatic hormone receptor-positive breast cancer. Our study suggests that HRG is a novel target for ERα-positive breast cancer therapy.


Asunto(s)
Neoplasias de la Mama/genética , Receptor alfa de Estrógeno/genética , Neurregulina-1 , Receptor ErbB-2/genética , Antineoplásicos Hormonales/farmacología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Antagonistas del Receptor de Estrógeno/farmacología , Receptor alfa de Estrógeno/metabolismo , Everolimus/farmacología , Femenino , Fulvestrant/farmacología , Humanos , Terapia Molecular Dirigida , Células Madre Neoplásicas/efectos de los fármacos , Sirolimus/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Resultado del Tratamiento
14.
J Steroid Biochem Mol Biol ; 202: 105697, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32461092

RESUMEN

Treatment of hormone sensitive breast cancer tumors with endocrine therapy such as antiestrogens or aromatase inhibitors has improved the outcome significantly. Studies including our own have shown that downregulation of ERα with pure antiestrogen fulvestrant in combination with aromatase inhibitors may prolong responsiveness of the tumors to endocrine therapy. Fulvestrant has been studied as second line or first line treatment for post-menopausal hormone receptor positive breast cancers as a single agent or in combination with AIs. Studies have also suggested that further escalation of dose may improve benefit. However, dose escalation of fulvestrant, which is administered via intramuscular injection, is difficult due to its poor solubility. To overcome this shortcoming of an injectable drug, a novel orally active antiestrogen, AZD9496 was developed. In addition to being orally active, AZD9496 is designed as a selective ERα downregulator (SERD). In the current study, we compared the effect of AZD9496 and fulvestrant on the growth of MCF-7Ca (human estrogen receptor positive MCF-7 cells stably transfected with human placental aromatase gene) xenografts grown in ovariectomized athymic nude mice. AZD9496 was also compared to fulvestrant in vitro as a single agent or in combination with anastrozole. Our current study shows that AZD9496 is equally effective as fulvestrant at controlling the growth of hormone sensitive human breast cancer tumors. Similar to fulvestrant, AZD9496 inhibits cellular aromatase activity through ERα mediated signaling. However, unlike fulvestrant, combination of AZD9496 with anastrozole did not produce increased tumor inhibition. Our results show that AZD9496 was significantly better at inhibiting cellular aromatase which contributed to its anticancer activity. Next, we measured the effect of AZD9496 on the mouse uterus. Uterine weight of mice treated with AZD9496 was significantly lower than that for mice treated with androstenedione. This reduction in uterine weight was due to AZD9496 mediated inhibition of aromatase activity and not a direct effect on uterine ERα expression. We also observed that anti-cancer efficacy of AZD9496 depended on its ability to inhibit cellular aromatase. These results suggest that AZD9496 may be a better alternative to fulvestrant due to its selectivity for mammary ER and ability to inhibit aromatase in addition of downregulating ERα that can be obtained upon oral administration. As such, AZD9496 may prove to be a better option than fulvestrant for the treatment of hormone sensitive human breast cancer.


Asunto(s)
Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Cinamatos/uso terapéutico , Indoles/uso terapéutico , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Moduladores Selectivos de los Receptores de Estrógeno/uso terapéutico , Anastrozol/farmacología , Anastrozol/uso terapéutico , Animales , Antineoplásicos Hormonales/farmacología , Antineoplásicos Hormonales/uso terapéutico , Aromatasa/metabolismo , Inhibidores de la Aromatasa/farmacología , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Cinamatos/farmacología , Antagonistas del Receptor de Estrógeno/farmacología , Antagonistas del Receptor de Estrógeno/uso terapéutico , Receptor alfa de Estrógeno , Femenino , Fulvestrant/farmacología , Fulvestrant/uso terapéutico , Humanos , Indoles/farmacología , Neoplasias Mamarias Experimentales/metabolismo , Ratones Desnudos , Posmenopausia , Moduladores Selectivos de los Receptores de Estrógeno/farmacología
15.
Oncol Rep ; 43(6): 2017-2027, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32323833

RESUMEN

Tamoxifen is widely used as a highly effective drug for treating estrogen­receptor (ER) alpha­positive breast cancer. However, tamoxifen resistance developed during cancer treatment remains a significant challenge. Tongue cancer resistance­related protein1 (TCRP1), which is recognized as a novel drug target, is related to chemo­resistance in human cancers, moreover, it is often overexpressed in various cancer cells, such as in lung cancer, breast cancer, and tongue cancer. However, the effects of TCRP1 on tamoxifen­resistant breast cancer cells and tissues are far from clear. The present study revealed that TCRP1 induced tamoxifen resistance in breast cancer cells. Western blotting, quantitative real­time polymerase chain reaction (RT­PCR) and immunohistochemical staining were performed to detect the expression level of TCRP1 in vivo and in vitro between primary breast cancer tissues and tamoxifen­resistant breast cancer tissues. The data revealed that the expression of TCRP1 was upregulated in the tamoxifen­resistant breast cancer tissues and human breast cancer cell line, MCF­7. Further study revealed that knocking down TCRP1 inhibited the growth of MCF­7 cells with tamoxifen­resistance (MCF7­R cells) and induced cell apoptosis. Moreover, TCRP1 promoted serum­ and glucocorticoid­inducible kinase 1 (SGK1) activation via phosphorylation of phosphoinositide­dependent kinase 1 (PDK1) in MCF7­R cells. In addition, it was also observed that knocking down TCRP1 inhibited tumorigenesis of MCF­7 cells in nude mice. In conclusion, these data indicated that TCRP1 could induce tamoxifen resistance by regulating the PDK1/SGK1 signaling pathway. Thus, TCRP1 could be explored as a promising candidate for treating tamoxifen­resistant breast cancer in the future.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Proteínas Inmediatas-Precoces/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas/metabolismo , Tamoxifeno/farmacología , Animales , Antineoplásicos Hormonales/farmacología , Apoptosis/efectos de los fármacos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos , Femenino , Humanos , Proteínas Inmediatas-Precoces/genética , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Proteínas Serina-Treonina Quinasas/genética , Proteínas/genética , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
16.
Cancer Cell ; 37(4): 496-513, 2020 04 13.
Artículo en Inglés | MEDLINE | ID: mdl-32289273

RESUMEN

Estrogen receptor-positive (ER+) breast cancer is the most common breast cancer subtype. Treatment of ER+ breast cancer comprises interventions that suppress estrogen production and/or target the ER directly (overall labeled as endocrine therapy). While endocrine therapy has considerably reduced recurrence and mortality from breast cancer, de novo and acquired resistance to this treatment remains a major challenge. An increasing number of mechanisms of endocrine resistance have been reported, including somatic alterations, epigenetic changes, and changes in the tumor microenvironment. Here, we review recent advances in delineating mechanisms of resistance to endocrine therapies and potential strategies to overcome such resistance.


Asunto(s)
Antineoplásicos Hormonales/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Resistencia a Antineoplásicos , Receptores Estrogénicos/metabolismo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Manejo de la Enfermedad , Femenino , Humanos , Microambiente Tumoral
17.
Zhonghua Zhong Liu Za Zhi ; 42(3): 192-196, 2020 Mar 23.
Artículo en Chino | MEDLINE | ID: mdl-32252196

RESUMEN

Luminal breast cancer is the most common subtype of breast cancer, representing more than 60% of all breast cancers. Endocrine resistance and late recurrence are two challenges in the treatment of luminal breast cancer. To overcome endocrine resistance in multiple levels, high-dose-fulvestrant can inhibit estrogen-receptor (ER)-dependent pathways, while targeted drugs can block ER-independent pathways.To reduce the risk of late recurrence in luminal breast cancer, recurrence prediction model should be formed. For patients with high risk of late recurrence, extended endocrine therapy, combination of ovarian function suppression (OFS) or vascular endothelial growth factor (VEGF) inhibitor could be utilized. Based on the challenges of the treatment, scientific research achievements can be used in clinical practice, and finally optimize the clinical treatment strategy.


Asunto(s)
Antineoplásicos Hormonales/uso terapéutico , Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Resistencia a Antineoplásicos , Moduladores de los Receptores de Estrógeno/uso terapéutico , Fulvestrant/uso terapéutico , Antineoplásicos Hormonales/farmacología , Neoplasias de la Mama/inmunología , Humanos , Recurrencia Local de Neoplasia , Receptores Estrogénicos/metabolismo , Factor A de Crecimiento Endotelial Vascular
18.
Biochim Biophys Acta Rev Cancer ; 1873(2): 188358, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32147544

RESUMEN

Breast cancer develops in the mammary glands during mammalian adulthood and is considered the second most common type of human carcinoma and the most incident and mortal in the female population. In contrast to other human structures, the female mammary glands continue to develop after birth, undergoing various modifications during pregnancy, lactation and involution under the regulation of hormones and transcription factors, including those encoded by the HOX clusters (A, B, C, and D). Interestingly, HOX gene deregulation is often associated to breast cancer development. Within the HOXB cluster, 8 out of the 10 genes present altered expression levels in breast cancer with an impact in its aggressiveness and resistance to hormone therapy, which highlights the importance of HOXB genes as potential therapeutic targets used to overcome the limitations of tamoxifen-resistant cancer treatments. Here, we review the current state of knowledge on the role of HOX genes in breast cancer, specially focus on HOXB, discussing the causes and consequences of HOXB gene deregulation and their relevance as prognostic factors and therapeutic targets.


Asunto(s)
Neoplasias de la Mama/genética , Regulación del Desarrollo de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Proteínas de Homeodominio/genética , Glándulas Mamarias Humanas/patología , Animales , Antineoplásicos Hormonales/farmacología , Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Resistencia a Antineoplásicos/genética , Femenino , Genes Homeobox , Proteínas de Homeodominio/metabolismo , Humanos , Glándulas Mamarias Animales/crecimiento & desarrollo , Glándulas Mamarias Animales/patología , Glándulas Mamarias Humanas/crecimiento & desarrollo , Estadificación de Neoplasias , Embarazo , Pronóstico
19.
J Steroid Biochem Mol Biol ; 200: 105641, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32151708

RESUMEN

The aromatase inhibitors (AIs), letrozole (Femar®/Femara®) and exemestane (Aromasin®), are widely used to treat estrogen receptor (ER) positive breast cancer in postmenopausal patients. In the setting of metastatic breast cancer, these drugs may be used after another causing new responses in selected patients after progressing on the first choice. The precise explanation for this "lack of cross resistance" is still missing. NEOLETEXE is a neoadjuvant, randomized, open-label, cross-over trial. Postmenopausal patients with ER-positive, HER-2 negative, locally advanced breast cancer were enrolled. All patients were randomized to treatment starting with either letrozole or exemestane for at least 2 months followed by another 2 months on the alternative AI. The total estrogenic activities in blood samples were determined using the AroER tri-screen assay developed in the Chen laboratory. Using this highly sensitive assay, estrogenic activity was detected at three time points for all patients. Importantly, a significantly higher total estrogenic activity was found during therapy with exemestane compared to letrozole in 21 out of 26 patients. When letrozole was included in the AroER tri-screen assay, the estrogenic activities in most samples collected during exemestane treatment were further reduced, suggesting that low levels of androgens remained in specimens obtained after exemestane treatment. Our results suggest the AroER tri-screen to be a very sensitive method to estimate the overall estrogen-mediated activity in human samples even during therapy with highly potent aromatase inhibitors. In the present study, serum estrogen activity was significantly higher during exemestane therapy when compared to letrozole therapy.


Asunto(s)
Androstadienos/farmacología , Antineoplásicos Hormonales/farmacología , Inhibidores de la Aromatasa/farmacología , Neoplasias de la Mama/sangre , Estradiol/sangre , Estrógenos/sangre , Letrozol/farmacología , Anciano , Anciano de 80 o más Años , Androstadienos/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Estudios Cruzados , Femenino , Humanos , Letrozol/uso terapéutico , Células MCF-7 , Persona de Mediana Edad , Terapia Neoadyuvante , Posmenopausia
20.
Breast Cancer Res ; 22(1): 16, 2020 02 03.
Artículo en Inglés | MEDLINE | ID: mdl-32014063

RESUMEN

BACKGROUND: Emerging mutations in the ESR1 gene that encodes for the estrogen receptor (ER) are associated with resistance to endocrine therapy. ESR1 mutations rarely exist in primary tumors (~ 1%) but are relatively common (10-50%) in metastatic, endocrine therapy-resistant cancers and are associated with a shorter progression-free survival. Little is known about the incidence and clinical implication of these mutations in early recurrence events, such as local recurrences or newly diagnosed metastatic disease. METHODS: We collected 130 archival tumor samples from 103 breast cancer patients treated with endocrine therapy prior to their local/metastatic recurrence. The cohort consisted of 41 patients having at least 1 sample from local/loco-regional recurrence and 62 patients with metastatic disease (of whom 41 newly diagnosed and 28 with advanced disease). The 5 most common ESR1 hotspot mutations (D538G, L536R, Y537S/N/C) were analyzed either by targeted sequencing or by droplet digital PCR. Progression-free survival (PFS), disease-free survival (DFS), and distant recurrence-free survival (DRFS) were statistically tested by Kaplan-Meier analysis. RESULTS: The prevalence of ESR1 mutations was 5/41 (12%) in newly diagnosed metastatic patients and 5/28 (18%) for advanced metastases, detected at allele frequency > 1%. All mutations in advanced metastases were detected in patients previously treated with both tamoxifen (TAM) and aromatase inhibitors (AI). However, in newly diagnosed metastatic patients, 4/5 mutations occurred in patients treated with TAM alone. PFS on AI treatment in metastatic patients was significantly shorter for ESR1 mutation carriers (p = 0.017). In the local recurrence cohort, ESR1 mutations were identified in 15/41 (36%) patients but only 4/41 (10%) were detected at allele frequency > 1%. Again, most mutations (3/4) were detected under TAM monotherapy. Notably, 1 patient developed ESR1 mutation while on neoadjuvant endocrine therapy. DFS and DRFS were significantly shorter (p = 0.04 and p = 0.017, respectively) in patients that had ESR1 mutations (> 1%) in their loco-regional recurrence tumor. CONCLUSIONS: Clinically relevant ESR1 mutations are prevalent in newly diagnosed metastatic and local recurrence of endocrine-treated breast cancer. Since local recurrences are amenable to curative therapy, these mutations may inform the selection of subsequent endocrine therapies.


Asunto(s)
Antineoplásicos Hormonales/farmacología , Neoplasias de la Mama/mortalidad , Resistencia a Antineoplásicos , Receptor alfa de Estrógeno/genética , Mutación , Recurrencia Local de Neoplasia/mortalidad , Neoplasias Hormono-Dependientes/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Femenino , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Neoplasias Hormono-Dependientes/tratamiento farmacológico , Neoplasias Hormono-Dependientes/genética , Neoplasias Hormono-Dependientes/patología , Tasa de Supervivencia , Resultado del Tratamiento
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