c-Myc dependent expression of pro-apoptotic Bim renders HER2-overexpressing breast cancer cells dependent on anti-apoptotic Mcl-1

Molecular Cancer

Research

Cécile Couriaud¹  Morgan Grau¹  Frédérique Braun¹  Yannis Guillemin¹  Sophie Barillé-Nion¹  Philippe Juin¹  Olivier Coqueret²  Benjamin Barré²  Mario Campone³  Bélinda Noël³  Fabien Gautier³  Pascal Jézéquel⁴  Loïc Campion⁵  Catherine Charbonnel⁵  Wilfried Gouraud⁵ 

[1] Centre de Recherche en Cancérologie Nantes-Angers - UMR 892 - INSERM/Université de Nantes, Institut de Recherche Thérapeutique de l'Université de Nantes, BP 7072144007, 8 Quai Moncousu, Nantes Cedex 1, France;Centre de Recherche en Cancérologie Nantes-Angers - UMR 892 - INSERM/Université de Nantes, Institut de Recherche Thérapeutique de l'Université de Nantes, BP 7072144007, 8 Quai Moncousu, Nantes Cedex 1, France;Institut de Cancérologie de l'Ouest, CLCC Paul Papin, 2 rue Moll, 49033, ANGERS, France;Centre de Recherche en Cancérologie Nantes-Angers - UMR 892 - INSERM/Université de Nantes, Institut de Recherche Thérapeutique de l'Université de Nantes, BP 7072144007, 8 Quai Moncousu, Nantes Cedex 1, France;Service d'Oncologie Médicale, Institut de Cancérologie de l'Ouest, CLCC René Gauducheau, Bd J. Monod, 44805, Nantes, Saint Herblain France;Unité Mixte de Génomique du Cancer, Hôpital Laënnec Bd J. Monod, 44805, Nantes, Saint Herblain Cedex France;Département de Biologie Oncologique, Institut de Cancérologie de l'Ouest, CLCC René Gauducheau, Bd J. Monod, 44805, Nantes, Saint Herblain France;Unité de Biostatistique et de Biologie Intégrée, Institut de Cancérologie de l'Ouest, CLCC René Gauducheau, Bd J. Monod, 44805, Nantes, Saint Herblain France;Unité Mixte de Génomique du Cancer, Hôpital Laënnec Bd J. Monod, 44805, Nantes, Saint Herblain Cedex France;

关键词: Human Epidermal Growth Factor Receptor;    HER2 Overexpressing;    BT474 Cell;    HER2 Overexpressing Breast Cancer;    RAD001 Treatment;   

DOI  :  10.1186/1476-4598-10-110

 received in 2011-02-02, accepted in 2011-09-07,  发布年份 2011

来源: Springer

【 摘 要 】

BackgroundAnti-apoptotic signals induced downstream of HER2 are known to contribute to the resistance to current treatments of breast cancer cells that overexpress this member of the EGFR family. Whether or not some of these signals are also involved in tumor maintenance by counteracting constitutive death signals is much less understood. To address this, we investigated what role anti- and pro-apoptotic Bcl-2 family members, key regulators of cancer cell survival, might play in the viability of HER2 overexpressing breast cancer cells.MethodsWe used cell lines as an in vitro model of HER2-overexpressing cells in order to evaluate how anti-apoptotic Bcl-2, Bcl-xL and Mcl-1, and pro-apoptotic Puma and Bim impact on their survival, and to investigate how the constitutive expression of these proteins is regulated. Expression of the proteins of interest was confirmed using lysates from HER2-overexpressing tumors and through analysis of publicly available RNA expression data.ResultsWe show that the depletion of Mcl-1 is sufficient to induce apoptosis in HER2-overexpressing breast cancer cells. This Mcl-1 dependence is due to Bim expression and it directly results from oncogenic signaling, as depletion of the oncoprotein c-Myc, which occupies regions of the Bim promoter as evaluated in ChIP assays, decreases Bim levels and mitigates Mcl-1 dependence. Consistently, a reduction of c-Myc expression by inhibition of mTORC1 activity abrogates occupancy of the Bim promoter by c-Myc, decreases Bim expression and promotes tolerance to Mcl-1 depletion. Western blot analysis confirms that naïve HER2-overexpressing tumors constitutively express detectable levels of Mcl-1 and Bim, while expression data hint on enrichment for Mcl-1 transcripts in these tumors.ConclusionsThis work establishes that, in HER2-overexpressing tumors, it is necessary, and maybe sufficient, to therapeutically impact on the Mcl-1/Bim balance for efficient induction of cancer cell death.

【 授权许可】

Unknown   
© Campone et al; licensee BioMed Central Ltd. 2011. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.