A BRCA1deficient-like signature is enriched in breast cancer brain metastases and predicts DNA damage-induced poly ADP-ribose polymerase inhibitor sensitivityReportar como inadecuado




A BRCA1deficient-like signature is enriched in breast cancer brain metastases and predicts DNA damage-induced poly ADP-ribose polymerase inhibitor sensitivity - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Breast Cancer Research

, 16:R25

First Online: 14 March 2014Received: 17 September 2013Accepted: 26 February 2014DOI: 10.1186-bcr3625

Cite this article as: McMullin, R.P., Wittner, B.S., Yang, C. et al. Breast Cancer Res 2014 16: R25. doi:10.1186-bcr3625

Abstract

IntroductionThere is an unmet clinical need for biomarkers to identify breast cancer patients at an increased risk of developing brain metastases. The objective is to identify gene signatures and biological pathways associated with human epidermal growth factor receptor 2-positive HER2+ brain metastasis.

MethodsWe combined laser capture microdissection and gene expression microarrays to analyze malignant epithelium from HER2+ breast cancer brain metastases with that from HER2+ nonmetastatic primary tumors. Differential gene expression was performed including gene set enrichment analysis GSEA using publicly available breast cancer gene expression data sets.

ResultsIn a cohort of HER2+ breast cancer brain metastases, we identified a gene expression signature that anti-correlates with overexpression of BRCA1. Sequence analysis of the HER2+ brain metastases revealed no pathogenic mutations of BRCA1, and therefore the aforementioned signature was designated BRCA1 Deficient-Like BD-L. Evaluation of an independent cohort of breast cancer metastases demonstrated that BD-L values are significantly higher in brain metastases as compared to other metastatic sites. Although the BD-L signature is present in all subtypes of breast cancer, it is significantly higher in BRCA1 mutant primary tumors as compared with sporadic breast tumors. Additionally, BD-L signature values are significantly higher in HER2-ER- primary tumors as compared with HER2+-ER + and HER2-ER + tumors. The BD-L signature correlates with breast cancer cell line pharmacologic response to a combination of poly ADP-ribose polymerase PARP inhibitor and temozolomide, and the signature outperformed four published gene signatures of BRCA1-2 deficiency.

ConclusionsA BD-L signature is enriched in HER2+ breast cancer brain metastases without pathogenic BRCA1 mutations. Unexpectedly, elevated BD-L values are found in a subset of primary tumors across all breast cancer subtypes. Evaluation of pharmacological sensitivity in breast cancer cell lines representing all breast cancer subtypes suggests the BD-L signature may serve as a biomarker to identify sporadic breast cancer patients who might benefit from a therapeutic combination of PARP inhibitor and temozolomide and may be indicative of a dysfunctional BRCA1-associated pathway.

AbbreviationsBD-L‘BRCA1 Deficient-Like’

ERestrogen receptor

GSEAgene set enrichment analysis

HER2+human epidermal growth factor receptor 2-positive

IHCimmunohistochemistry

MBCmetastatic breast cancer

MSigDBMolecular Signatures Database

PARPpoly ADP-ribose polymerase.

Electronic supplementary materialThe online version of this article doi:10.1186-bcr3625 contains supplementary material, which is available to authorized users.

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Autor: Ryan P McMullin - Ben S Wittner - Chuanwei Yang - Benjamin R Denton-Schneider - Daniel Hicks - Raj Singavarapu - Sharon 

Fuente: https://link.springer.com/







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