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1.
Nat Commun ; 12(1): 6967, 2021 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-34845227

RESUMO

Breast cancer is now globally the most frequent cancer and leading cause of women's death. Two thirds of breast cancers express the luminal estrogen receptor-positive (ERα + ) phenotype that is initially responsive to antihormonal therapies, but drug resistance emerges. A major barrier to the understanding of the ERα-pathway biology and therapeutic discoveries is the restricted repertoire of luminal ERα + breast cancer models. The ERα + phenotype is not stable in cultured cells for reasons not fully understood. We examine 400 patient-derived breast epithelial and breast cancer explant cultures (PDECs) grown in various three-dimensional matrix scaffolds, finding that ERα is primarily regulated by the matrix stiffness. Matrix stiffness upregulates the ERα signaling via stress-mediated p38 activation and H3K27me3-mediated epigenetic regulation. The finding that the matrix stiffness is a central cue to the ERα phenotype reveals a mechanobiological component in breast tissue hormonal signaling and enables the development of novel therapeutic interventions. Subject terms: ER-positive (ER + ), breast cancer, ex vivo model, preclinical model, PDEC, stiffness, p38 SAPK.


Assuntos
Neoplasias da Mama/genética , Receptor alfa de Estrogênio/genética , Mecanotransdução Celular/genética , Transcriptoma , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Linhagem Celular Tumoral , Cinamatos/farmacologia , Colágeno/química , Colágeno/farmacologia , Combinação de Medicamentos , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Estradiol/farmacologia , Receptor alfa de Estrogênio/metabolismo , Feminino , Fulvestranto/farmacologia , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Histonas/genética , Histonas/metabolismo , Humanos , Indazóis/farmacologia , Laminina/química , Laminina/farmacologia , Glândulas Mamárias Humanas/efeitos dos fármacos , Glândulas Mamárias Humanas/metabolismo , Glândulas Mamárias Humanas/patologia , Fenótipo , Proteoglicanas/química , Proteoglicanas/farmacologia , Tamoxifeno/farmacologia , Técnicas de Cultura de Tecidos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
3.
Nat Commun ; 10(1): 620, 2019 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-30728358

RESUMO

Elevated MYC expression sensitizes tumor cells to apoptosis but the therapeutic potential of this mechanism remains unclear. We find, in a model of MYC-driven breast cancer, that pharmacological activation of AMPK strongly synergizes with BCL-2/BCL-XL inhibitors to activate apoptosis. We demonstrate the translational potential of an AMPK and BCL-2/BCL-XL co-targeting strategy in ex vivo and in vivo models of MYC-high breast cancer. Metformin combined with navitoclax or venetoclax efficiently inhibited tumor growth, conferred survival benefits and induced tumor infiltration by immune cells. However, withdrawal of the drugs allowed tumor re-growth with presentation of PD-1+/CD8+ T cell infiltrates, suggesting immune escape. A two-step treatment regimen, beginning with neoadjuvant metformin+venetoclax to induce apoptosis and followed by adjuvant metformin+venetoclax+anti-PD-1 treatment to overcome immune escape, led to durable antitumor responses even after drug withdrawal. We demonstrate that pharmacological reactivation of MYC-dependent apoptosis is a powerful antitumor strategy involving both tumor cell depletion and immunosurveillance.


Assuntos
Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Genes myc/efeitos dos fármacos , Imunoterapia , Compostos de Anilina/farmacologia , Animais , Anticorpos Monoclonais Humanizados , Apoptose/imunologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Linfócitos T CD8-Positivos , Linhagem Celular Tumoral/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Combinação de Medicamentos , Feminino , Células HEK293 , Xenoenxertos , Humanos , Metformina/farmacologia , Camundongos , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-bcl-2 , Sulfonamidas/farmacologia , Proteína bcl-X
4.
Methods Mol Biol ; 1731: 169-178, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29318553

RESUMO

Breakdown of the basement membrane is a key step that precedes tumor invasion, and accumulating evidence suggests a key role for the type II transmembrane proteases (TTSPs) in that process. Overexpression of a TTSP hepsin characterizes many solid cancers, including prostate, breast, and ovarian cancer, and in experimental tumor models, the elevated proteolytic activity of hepsin simultaneously activates several growth factors and cleaves basement membrane protein laminin-332, which is an essential component of the cell-basement membrane junction hemidesmosome. These hepsin-dependent molecular events associate with dramatic loss of basement membrane integrity in mouse tumor models and in three-dimensional (3D) epithelial culture. In particular, the 3D culture systems offer unprecedented possibilities to clarify the mechanistic basis of destructive interactions between out-of-control serine protease activity and the basement membrane structure. Here, we describe how to establish 3D mammary epithelial culture in an exogenous basement membrane-free egg white matrix and provide a protocol for quantitative analysis of the impact of hepsin on laminin-332 and its hemidesmosomal receptor α6-integrin by means of confocal microscopy imaging. These protocols were established to facilitate studies aiming to decipher the exact role of oncogenic proteases in tumor invasion processes and to identify novel therapeutic agents able to intervene these cancer critical processes.


Assuntos
Membrana Basal/metabolismo , Técnicas de Cultura de Células/métodos , Serina Endopeptidases/metabolismo , Moléculas de Adesão Celular/metabolismo , Técnicas de Cultura de Células/instrumentação , Linhagem Celular Tumoral , Células Epiteliais , Humanos , Microscopia Confocal/instrumentação , Microscopia Confocal/métodos , Calinina
5.
Viruses ; 9(10)2017 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-28946654

RESUMO

Viral diseases remain serious threats to public health because of the shortage of effective means of control. To combat the surge of viral diseases, new treatments are urgently needed. Here we show that small-molecules, which inhibit cellular anti-apoptotic Bcl-2 proteins (Bcl-2i), induced the premature death of cells infected with different RNA or DNA viruses, whereas, at the same concentrations, no toxicity was observed in mock-infected cells. Moreover, these compounds limited viral replication and spread. Surprisingly, Bcl-2i also induced the premature apoptosis of cells transfected with viral RNA or plasmid DNA but not of mock-transfected cells. These results suggest that Bcl-2i sensitizes cells containing foreign RNA or DNA to apoptosis. A comparison of the toxicity, antiviral activity, and side effects of six Bcl-2i allowed us to select A-1155463 as an antiviral lead candidate. Thus, our results pave the way for the further development of Bcl-2i for the prevention and treatment of viral diseases.


Assuntos
Antivirais/farmacologia , Apoptose/efeitos dos fármacos , Benzotiazóis/farmacologia , Isoquinolinas/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Replicação Viral/efeitos dos fármacos , Vírus/efeitos dos fármacos , Compostos de Anilina/farmacologia , Antivirais/química , Antivirais/uso terapêutico , Benzotiazóis/química , Benzotiazóis/uso terapêutico , Linhagem Celular , DNA Viral/genética , Humanos , Isoquinolinas/química , Isoquinolinas/uso terapêutico , Metabolômica , RNA Viral/genética , Sulfonamidas/farmacologia , Transfecção , Viroses/tratamento farmacológico , Viroses/prevenção & controle
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