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Roles of the protein tyrosine phosphatase SHP2 in metastatic breast cancer

English title Roles of the protein tyrosine phosphatase SHP2 in metastatic breast cancer
Applicant Bentires-Alj Mohamed
Number 143372
Funding scheme Project funding (Div. I-III)
Research institution Friedrich Miescher Institute for Biomedical Research
Institution of higher education Institute Friedrich Miescher - FMI
Main discipline Experimental Cancer Research
Start/End 01.07.2013 - 30.11.2016
Approved amount 555'051.00
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Keywords (1)

breast cancer metastases. Phosphatases. SHP2

Lay Summary (French)

Lead
Rôles de la protéine tyrosine phosphatase SHP2 dans le cancer du sein métastatique
Lay summary
 

Chaque année le cancer du sein est diagnostiqué chez plus d’un million de femmes dans le monde et plus de 450 000 patientes succombent à cette maladie. De nouvelles thérapies émergeront d’une meilleure compréhension des modifications des voies de signalisations dans les cellules cancéreuses.

Nos travaux montrent que la protéine tyrosine phosphatase SHP2 induit la prolifération des cellules cancéreuses du sein, contribue à leurs propriétés invasives quand elles sont cultivées en trois dimensions et joue un rôle important dans la maintenance et la propagation des tumeurs in vivo. Les effets de SHP2 sont relayés par la voie de signalisation Erk et peuvent être antagonisés par l’inhibition de cette voie de signalisation.

            De nombreuses questions ont émergé de ces travaux initiaux et font l’objet de ce projet. Nos objectifs principaux sont :

1- L’identification du/des substrat(s) de SHP2 dans le cancer du sein.

2- La détermination du rôle de SHP2 dans la dissémination métastatique liée au cancer mammaire.

3- La détermination de l’effet de l’inhibition de SHP2 dans les métastases.

 

Les résultats de nos recherches devront participer à l’implémentation et/ou le développement rationnel de thérapies ciblées et à une amélioration de la prise en charge thérapeutiques des patientes ayant un cancer du sein.

Direct link to Lay Summary Last update: 18.09.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Tyrosine phosphatase SHP2 increases cell motility in triple-negative breast cancer through the activation of SRC-family kinases.
Sausgruber N, Coissieux M-M, Britschgi A, Wyckoff J, Aceto N, Leroy C, Stadler M B, Voshol H, Bonenfant D, Bentires-Alj M (2015), Tyrosine phosphatase SHP2 increases cell motility in triple-negative breast cancer through the activation of SRC-family kinases., in Oncogene, 34(17), 2272-8.
Cessation of CCL2 inhibition accelerates breast cancer metastasis by promoting angiogenesis.
Bonapace Laura, Coissieux Marie-May, Wyckoff Jeffrey, Mertz Kirsten D, Varga Zsuzsanna, Junt Tobias, Bentires-Alj Mohamed (2014), Cessation of CCL2 inhibition accelerates breast cancer metastasis by promoting angiogenesis., in Nature, 515(7525), 130-3.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Search Breast cancer Glasgow Individual talk Cancer targeted therapy and tumor heterogeneity: Act locally, think globally 04.03.2016 Glasgow, Great Britain and Northern Ireland Bentires-Alj Mohamed;
Institut Gustave Roussy seminars Individual talk Cancer targeted therapy and tumor heterogeneity: Act locally, think globally 11.02.2016 Paris, France Bentires-Alj Mohamed;
Merck seminars at Mainz Individual talk Cancer targeted therapy and tumor heterogeneity: Act locally, think globally 14.01.2016 Mainz, Germany Bentires-Alj Mohamed;
EU-Life lecture: Institut Curie, Paris, France Individual talk Breast tumor heterogeneity and cancer targeted therapy 14.12.2015 Paris, France Bentires-Alj Mohamed;
Bellinzona cancer research retreat Talk given at a conference Cancer targeted therapy and tumor heterogeneity: Act locally, think globally 11.11.2015 Bellinzona, Switzerland Bentires-Alj Mohamed;
ETH seminars Individual talk Cancer targeted therapy and tumor heterogeneity: Act locally, think globally 25.02.2015 Zurich, Switzerland Bentires-Alj Mohamed;


Awards

Title Year
Elected European Molecular Biology Organization (EMBO) member 2016
AACR Outstanding Investigator in Breast Cancer Research Award 2015
Robert Wenner Award of the Swiss cancer league 2014
Susan G. Komen for the Cure EACR award 2014

Associated projects

Number Title Start Funding scheme
166428 Molecular mechanisms of breast tumorigenesis, metastasis, and resistance to therapy in tumors with a mutated PI3K pathway 01.12.2016 Project funding (Div. I-III)
184673 Molecular mechanisms underlying normal and neoplastic mammary stem cells, progression to metastasis and resistance to therapy 01.12.2019 Project funding (Div. I-III)

Abstract

Breast cancer ranks second among cancer deaths in women. Each year, this disease is diagnosed in over one million women worldwide and more than 400,000 lives are lost. Although progress has been made, we still do not understand the biology of breast cancer at a level that would explain why certain patients react well to therapy, whereas for others the disease is recurrent, with an inexorable downhill course. Improved treatment options are urgently needed to end this stalemate. New therapies are likely to arise only from a more comprehensive understanding of the “wiring diagram” of breast cancer cells. This proposal focuses on the role of the protein tyrosine phosphatase (PTP) SHP2 in breast cancer metastasis and comprises two parallel approaches. The first aims to define the substrate(s) of SHP2 in breast cancer. The second addresses the roles of SHP2 in metastatic spread and assesses its merits as a therapeutic target in established breast cancer metastases.Virtually all cell signaling pathways are modulated by reversible protein tyrosine phosphorylation, which is regulated by two classes of enzymes, the protein tyrosine kinases (PTKs) and PTPs. Not surprisingly, tyrosine phosphorylation has an important role in breast cancer. Whereas the involvement of specific PTKs in breast cancer, such as the HER2 receptor, has been well studied, the functions of specific PTPs in this disease are only now beginning to be elucidated. SHP2 is a ubiquitously expressed PTP that transduces mitogenic, prosurvival, cell fate and/or pro-migratory signals from almost all growth factor, cytokine and extracellular matrix receptors. It is required for the full activation of the ERK/MAPK pathway downstream of most receptors and has been shown to play a broad role in development, cell fate and tumorigenesis. We have discovered recently that SHP2 plays a fundamental role in tumor maintenance and progression in HER2-positive and triple-negative breast cancers, two subtypes associated with a poor prognosis. Knockdown of SHP2 prevented invasion in 3D cultures and eradicated breast tumor initiating cells (TICs) in vitro and in xenografts. Importantly, SHP2 knockdown in established breast tumors blocked growth and reduced metastases. Notably, these effects of SHP2 are dependent on the activation of the ERK pathway. These observations provoke further critical questions. What is/are the substrate(s) of SHP2 in breast cancer? How does SHP2 knockdown in primary tumors reduce metastases? Can SHP2 inhibition in established metastases block their growth? To answer these questions, we have set up unbiased phospho-proteomic approaches and established an intravital multiphoton microscope for imaging fluorescently labeled metastatic breast cancer cells expressing or lacking SHP2. These studies use state-of-the-art ex vivo and in vivo approaches to address the role of SHP2 in metastatic breast cancer and should lead ultimately to the rational design of targeted therapies that will improve the clinical management of patients.Our specific aims are:1- To identify the substrate(s) of SHP2 in breast cancer2- To determine the mechanism of action of SHP2 in metastasis3- To assess the effect of SHP2 knockdown in established breast cancer metastases.
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