Biologie du cancer du sein

Publications

Année de publication : 2016

Tina Gruosso, Virginie Mieulet, Melissa Cardon, Brigitte Bourachot, Yann Kieffer, Flavien Devun, Thierry Dubois, Marie Dutreix, Anne Vincent-Salomon, Kyle Malcolm Miller, Fatima Mechta-Grigoriou (2016 Mar 24)

Chronic oxidative stress promotes H2AX protein degradation and enhances chemosensitivity in breast cancer patients.

EMBO molecular medicine : 527-49 : DOI : 10.15252/emmm.201505891 En savoir plus
Résumé

Anti-cancer drugs often increase reactive oxygen species (ROS) and cause DNA damage. Here, we highlight a new cross talk between chronic oxidative stress and the histone variant H2AX, a key player in DNA repair. We observe that persistent accumulation of ROS, due to a deficient JunD-/Nrf2-antioxidant response, reduces H2AX protein levels. This effect is mediated by an enhanced interaction of H2AX with the E3 ubiquitin ligase RNF168, which is associated with H2AX poly-ubiquitination and promotes its degradation by the proteasome. ROS-mediated H2AX decrease plays a crucial role in chemosensitivity. Indeed, cycles of chemotherapy that sustainably increase ROS reduce H2AX protein levels in Triple-Negative breast cancer (TNBC) patients. H2AX decrease by such treatment is associated with an impaired NRF2-antioxidant response and is indicative of the therapeutic efficiency and survival of TNBC patients. Thus, our data describe a novel ROS-mediated regulation of H2AX turnover, which provides new insights into genetic instability and treatment efficacy in TNBC patients.

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Christophe Couderc, Alizée Boin, Laetitia Fuhrmann, Anne Vincent-Salomon, Vinay Mandati, Yann Kieffer, Fatima Mechta-Grigoriou, Laurence Del Maestro, Philippe Chavrier, David Vallerand, Isabelle Brito, Thierry Dubois, Leanne De Koning, Daniel Bouvard, Daniel Louvard, Alexis Gautreau, Dominique Lallemand (2016 Jan 26)

AMOTL1 integrates Hippo signaling to promote breast cancer progression by inducing tumor cell proliferation and migration

Neoplasia (New York, N.Y.) : 10-24 : DOI : 10.1016/j.neo.2015.11.010 En savoir plus
Résumé

The Hippo signaling network is a key regulator of cell fate. In the recent years, it was shown that its implication in cancer goes well beyond the sole role of YAP transcriptional activity and its regulation by the canonical MST/LATS kinase cascade. Here we show that the motin family member AMOTL1 is an important effector of Hippo signaling in breast cancer. AMOTL1 connects Hippo signaling to tumor cell aggressiveness. We show that both canonical and noncanonical Hippo signaling modulates AMOTL1 levels. The tumor suppressor Merlin triggers AMOTL1 proteasomal degradation mediated by the NEDD family of ubiquitin ligases through direct interaction. In parallel, YAP stimulates AMOTL1 expression. The loss of Merlin expression and the induction of Yap activity that are frequently observed in breast cancers thus result in elevated AMOTL1 levels. AMOTL1 expression is sufficient to trigger tumor cell migration and stimulates proliferation by activating c-Src. In a large cohort of human breast tumors, we show that AMOTL1 protein levels are upregulated during cancer progression and that, importantly, the expression of AMOTL1 in lymph node metastasis appears predictive of the risk of relapse. Hence we uncover an important mechanism by which Hippo signaling promotes breast cancer progression by modulating the expression of AMOTL1.

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Magali Michaut, Suet-Feung Chin, Ian Majewski, Tesa M Severson, Tycho Bismeijer, Leanne de Koning, Justine K Peeters, Philip C Schouten, Oscar M Rueda, Astrid J Bosma, Finbarr Tarrant, Yue Fan, Beilei He, Zheng Xue, Lorenza Mittempergher, Roelof J C Kluin, Jeroen Heijmans, Mireille Snel, Bernard Pereira, Andreas Schlicker, Elena Provenzano, Hamid Raza Ali, Alexander Gaber, Gillian O'Hurley, Sophie Lehn, Jettie J F Muris, Jelle Wesseling, Elaine Kay, Stephen John Sammut, Helen A Bardwell, Aurélie S Barbet, Floriane Bard, Caroline Lecerf, Darran P O'Connor, Daniël J Vis, Cyril H Benes, Ultan McDermott, Mathew J Garnett, Iris M Simon, Karin Jirström, Thierry Dubois, Sabine C Linn, William M Gallagher, Lodewyk F A Wessels, Carlos Caldas, Rene Bernards (2016 Jan 6)

Integration of genomic, transcriptomic and proteomic data identifies two biologically distinct subtypes of invasive lobular breast cancer.

Scientific reports : 18517 : DOI : 10.1038/srep18517 En savoir plus
Résumé

Invasive lobular carcinoma (ILC) is the second most frequently occurring histological breast cancer subtype after invasive ductal carcinoma (IDC), accounting for around 10% of all breast cancers. The molecular processes that drive the development of ILC are still largely unknown. We have performed a comprehensive genomic, transcriptomic and proteomic analysis of a large ILC patient cohort and present here an integrated molecular portrait of ILC. Mutations in CDH1 and in the PI3K pathway are the most frequent molecular alterations in ILC. We identified two main subtypes of ILCs: (i) an immune related subtype with mRNA up-regulation of PD-L1, PD-1 and CTLA-4 and greater sensitivity to DNA-damaging agents in representative cell line models; (ii) a hormone related subtype, associated with Epithelial to Mesenchymal Transition (EMT), and gain of chromosomes 1q and 8q and loss of chromosome 11q. Using the somatic mutation rate and eIF4B protein level, we identified three groups with different clinical outcomes, including a group with extremely good prognosis. We provide a comprehensive overview of the molecular alterations driving ILC and have explored links with therapy response. This molecular characterization may help to tailor treatment of ILC through the application of specific targeted, chemo- and/or immune-therapies.

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Année de publication : 2015

Elodie Manié, Tatiana Popova, Aude Battistella, Julien Tarabeux, Virginie Caux-Moncoutier, Lisa Golmard, Nicholas K Smith, Christopher R Mueller, Odette Mariani, Brigitte Sigal-Zafrani, Thierry Dubois, Anne Vincent-Salomon, Claude Houdayer, Dominique Stoppa-Lyonnet, Marc-Henri Stern (2015 Aug 29)

Genomic hallmarks of homologous recombination deficiency in invasive breast carcinomas.

International journal of cancer : 891-900 : DOI : 10.1002/ijc.29829 En savoir plus
Résumé

Therapeutic strategies targeting Homologous Recombination Deficiency (HRD) in breast cancer requires patient stratification. The LST (Large-scale State Transitions) genomic signature previously validated for triple-negative breast carcinomas (TNBC) was evaluated as biomarker of HRD in luminal (hormone receptor positive) and HER2-overexpressing (HER2+) tumors. The LST genomic signature related to the number of large-scale chromosomal breakpoints in SNP-array tumor profile was applied to identify HRD in in-house and TCGA sets of breast tumors, in which the status of BRCA1/2 and other genes was also investigated. In the in-house dataset, HRD was predicted in 5% (20/385) of sporadic tumors luminal or HER2+ by the LST genomic signature and the inactivation of BRCA1, BRCA2 or RAD51C confirmed this prediction in 75% (12/16) of the tested cases. In 14% (6/43) of tumors occurring in BRCA1/2 mutant carriers, the corresponding wild-type allele was retained emphasizing the importance of determining the tumor status. In the TCGA luminal and HER2+ subtypes HRD incidence was estimated at 5% (18/329, 95%CI: 5-8%) and 2% (1/59, 95%CI: 2-9%), respectively. In TNBC cisplatin-based neo-adjuvant clinical trials, HRD is shown to be a necessary condition for cisplatin sensitivity. This analysis demonstrates the high performance of the LST genomic signature for HRD detection in breast cancers, which suggests its potential as a biomarker for genetic testing and patient stratification for clinical trials evaluating platinum salts and PARP inhibitors.

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