SRC Increases MYC mRNA Expression in Estrogen Receptor-Positive Breast Cancer via mRNA Stabilization and Inhibition of p53 Function

ABSTRACT

The transcription factor gene MYC is important in breast cancer, and its mRNA is maintained at a high level even in the absence of gene amplification. The mechanism(s) underlying increased MYC mRNA expression is unknown. Here, we demonstrate that MYC mRNA was stabilized upon estrogen stimulation of estrogen receptor-positive breast cancer cells via SRC-dependent effects on a recently described RNA-binding protein, IMP1 with an N-terminal deletion (ΔN-IMP1). We also show that loss of the tumor suppressor p53 increased MYC mRNA levels even in the absence of estrogen stimulation. However, in cells with wild-type p53, SRC acted to overcome p53-mediated inhibition of estrogen-stimulated cell cycle entry and progression. SRC thus promotes cell proliferation in two ways: by stabilizing MYC mRNA and by inhibiting p53 function. Since estrogen receptor-positive breast cancers typically express wild-type p53, these studies establish a rationale for p53 status to be predictive for effective SRC inhibitor treatment in this subtype of breast cancer.

KEYWORDS:

• SRC
• breast cancer
• c-myc
• estrogen
• p53

View publisher note:

Articles of Significant Interest Selected from This Issue by the Editors

ACKNOWLEDGMENTS

We thank Leanne Jones for the pLKO.1-shIMP1 (sh8079) construct and Robert Oshima for the pLKO.1-shSRC and shYES constructs. We thank Julie Sadino and Ronn Leon for their assistance with the mouse xenograft experiments. Human cell line authentication assays were performed in the OHSU DNA Services Core.

This work was supported by a grant from the National Cancer Institute (R21CA177382) to S.A.C. and a predoctoral fellowship from the National Institutes of Health (F31CA180740) to C.A.

We declare that we have no conflicts of interest.

C.A. designed and performed experiments, analyzed data, and wrote the manuscript; H.K. designed and performed pilot experiments. S.I. cloned constructs and assisted on in vivo experiments. S.A.C. planned and designed experiments, wrote the manuscript, and had overall responsibility for the study.