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KSR1 regulates BRCA1 degradation and inhibits breast cancer growth

Stebbing, Justin; Zhang, Hua; Xu, Y.; Lit, Lei Cheng; Green, A.R.; Grothey, A.; Lombardo, Y.; Periyasamy, M.; Blighe, K.; Zhang, W.; Shaw, J.A.; Ellis, I.O.; Lenz, H.J.; Giamas, G.


Justin Stebbing

Hua Zhang

Y. Xu

Lei Cheng Lit

A. Grothey

Y. Lombardo

M. Periyasamy

K. Blighe

W. Zhang

J.A. Shaw

H.J. Lenz

G. Giamas


Kinase suppressor of Ras-1 (KSR1) facilitates signal transduction in Ras-dependent cancers, including pancreatic and lung carcinomas but its role in breast cancer has not been well studied. Here, we demonstrate for the first time it functions as a tumor suppressor in breast cancer in contrast to data in other tumors. Breast cancer patients (n>1000) with high KSR1 showed better disease-free and overall survival, results also supported by Oncomine analyses, microarray data (n=2878) and genomic data from paired tumor and cell-free DNA samples revealing loss of heterozygosity. KSR1 expression is associated with high breast cancer 1, early onset (BRCA1), high BRCA1-associated ring domain 1 (BARD1) and checkpoint kinase 1 (Chk1) levels. Phospho-profiling of major components of the canonical Ras-RAF-mitogen-activated protein kinases pathway showed no significant changes after KSR1 overexpression or silencing. Moreover, KSR1 stably transfected cells formed fewer and smaller size colonies compared to the parental ones, while in vivo mouse model also demonstrated that the growth of xenograft tumors overexpressing KSR1 was inhibited. The tumor suppressive action of KSR1 is BRCA1 dependent shown by 3D-matrigel and soft agar assays. KSR1 stabilizes BRCA1 protein levels by reducing BRCA1 ubiquitination through increasing BARD1 abundance. These data link these proteins in a continuum with clinical relevance and position KSR1 in the major oncoprotein pathways in breast tumorigenesis.


Stebbing, J., Zhang, H., Xu, Y., Lit, L. C., Green, A., Grothey, A., …Giamas, G. (2015). KSR1 regulates BRCA1 degradation and inhibits breast cancer growth. Oncogene, 34(16), 2103-2114.

Journal Article Type Article
Acceptance Date Apr 12, 2014
Online Publication Date Jun 9, 2014
Publication Date 2015-04
Deposit Date Oct 18, 2018
Publicly Available Date Nov 6, 2018
Journal Oncogene
Print ISSN 0950-9232
Electronic ISSN 1476-5594
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 34
Issue 16
Pages 2103-2114
Public URL
Publisher URL