Proteomic profile of KSR1-regulated signalling in response to genotoxic agents in breast cancer

Zhang, Hua, Angelopoulos, Nicos, Xu, Yichen, Grothey, Arnhild, Nunes, Joao, Stebbing, Justin and Giamas, Georgios (2015) Proteomic profile of KSR1-regulated signalling in response to genotoxic agents in breast cancer. Breast Cancer Research and Treatment, 151 (3). pp. 555-568. ISSN 0167-6806

[img]
Preview
PDF
Download (3MB) | Preview

Abstract

Kinase suppressor of Ras 1 (KSR1) has been implicated in tumorigenesis in multiple cancers, including skin, pancreatic and lung carcinomas. However, our recent study revealed a role of KSR1 as a tumour suppressor in breast cancer, the expression of which is potentially correlated with chemotherapy response. Here, we aimed to further elucidate the KSR1-regulated signalling in response to genotoxic agents in breast cancer. Stable isotope labelling by amino acids in cell culture (SILAC) coupled to high-resolution mass spectrometry (MS) was implemented to globally characterise cellular protein levels induced by KSR1 in the presence of doxorubicin or etoposide. The acquired proteomic signature was compared and GO-STRING analysis was subsequently performed to illustrate the activated functional signalling networks. Furthermore, the clinical associations of KSR1 with identified targets and their relevance in chemotherapy response were examined in breast cancer patients. We reveal a comprehensive repertoire of thousands of proteins identified in each dataset and compare the unique proteomic profiles as well as functional connections modulated by KSR1 after doxorubicin (Doxo-KSR1) or etoposide (Etop-KSR1) stimulus. From the up-regulated top hits, several proteins, including STAT1, ISG15 and TAP1 are also found to be positively associated with KSR1 expression in patient samples. Moreover, high KSR1 expression, as well as high abundance of these proteins, is correlated with better survival in breast cancer patients who underwent chemotherapy. In aggregate, our data exemplify a broad functional network conferred by KSR1 with genotoxic agents and highlight its implication in predicting chemotherapy response in breast cancer.

Item Type: Article
Schools and Departments: School of Life Sciences > Biochemistry
Subjects: Q Science > QH Natural history > QH0301 Biology
Depositing User: Georgios Giamas
Date Deposited: 07 Jul 2015 08:30
Last Modified: 07 Mar 2017 10:09
URI: http://sro.sussex.ac.uk/id/eprint/55213

View download statistics for this item

📧 Request an update