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 GOSTRING
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.