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

Abstract

The transcription factor gene <i>MYC</i> 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 <i>MYC</i> mRNA expression is unknown. Here, we demonstrate that <i>MYC</i> 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 <i>MYC</i> 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 <i>MYC</i> 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.