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Nat Commun ; 12(1): 4919, 2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34389725


BRCA1 or BRCA2 germline mutations predispose to breast, ovarian and other cancers. High-throughput sequencing of tumour genomes revealed that oncogene amplification and BRCA1/2 mutations are mutually exclusive in cancer, however the molecular mechanism underlying this incompatibility remains unknown. Here, we report that activation of ß-catenin, an oncogene of the WNT signalling pathway, inhibits proliferation of BRCA1/2-deficient cells. RNA-seq analyses revealed ß-catenin-induced discrete transcriptome alterations in BRCA2-deficient cells, including suppression of CDKN1A gene encoding the CDK inhibitor p21. This accelerates G1/S transition, triggering illegitimate origin firing and DNA damage. In addition, ß-catenin activation accelerates replication fork progression in BRCA2-deficient cells, which is critically dependent on p21 downregulation. Importantly, we find that upregulated p21 expression is essential for the survival of BRCA2-deficient cells and tumours. Thus, our work demonstrates that ß-catenin toxicity in cancer cells with compromised BRCA1/2 function is driven by transcriptional alterations that cause aberrant replication and inflict DNA damage.

Proteína BRCA1/genética , Proteína BRCA2/genética , Oncogenes/genética , Transcrição Genética/genética , beta Catenina/genética , Proteína BRCA1/deficiência , Proteína BRCA2/deficiência , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Sobrevivência Celular/genética , Células Cultivadas , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Dano ao DNA , Feminino , Perfilação da Expressão Gênica/métodos , Células HeLa , Humanos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , RNA-Seq/métodos , beta Catenina/metabolismo
Mol Cell ; 80(1): 21-28, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32810436


Cancer immunotherapies enhance anti-tumor immune responses using checkpoint inhibitors, such as PD-1 or PD-L1 inhibitors. Recent studies, however, have extended the scope of immunotherapeutics by unveiling DNA damage-induced innate immunity as a novel target for cancer treatment. Elucidating the interplay among the DNA damage response (DDR), cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway activation, and anti-tumoral immunity is critical for the development of effective cancer immunotherapies. Here, we discuss the current understanding of the mechanisms by which DNA damage activates immune responses that target and eradicate cancer cells. Yet, understanding how cancer cells can escape this immune surveillance and promote tumor progression represents an outstanding challenge. We highlight the most recent clinical advances, in particular how pharmacological fine-tuning of innate/adaptive immunity and its combination with DDR inhibitors, ionizing radiation (IR), and chemotherapy can be exploited to improve cancer treatment.

Dano ao DNA , Imunoterapia , Proteínas de Membrana/metabolismo , Neoplasias/patologia , Neoplasias/terapia , Instabilidade Genômica , Humanos , Imunidade Inata , Neoplasias/genética , Neoplasias/imunologia
Nat Commun ; 10(1): 3143, 2019 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-31316060


Heterozygous germline mutations in BRCA2 predispose to breast and ovarian cancer. Contrary to non-cancerous cells, where BRCA2 deletion causes cell cycle arrest or cell death, tumors carrying BRCA2 inactivation continue to proliferate. Here we set out to investigate adaptation to loss of BRCA2 focusing on genome-wide transcriptome alterations. Human cells in which BRCA2 expression is inhibited for 4 or 28 days are subjected to RNA-seq analyses revealing a biphasic response to BRCA2 abrogation. The early, acute response consists of downregulation of genes involved in cell cycle progression, DNA replication and repair and is associated with cell cycle arrest in G1. Surprisingly, the late, chronic response consists predominantly of upregulation of interferon-stimulated genes (ISGs). Activation of the cGAS-STING-STAT pathway detected in these cells further substantiates the concept that BRCA2 abrogation triggers cell-intrinsic immune signaling. Importantly, we find that treatment with PARP inhibitors stimulates the interferon response in cells and tumors lacking BRCA2.

Proteína BRCA2/genética , Neoplasias da Mama/genética , Animais , Neoplasias da Mama/imunologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Dano ao DNA , Reparo do DNA , Feminino , Deleção de Genes , Regulação Neoplásica da Expressão Gênica , Humanos , Imunidade Inata , Camundongos SCID , Ftalazinas/farmacologia , Piperazinas/farmacologia