SRC increases MYC mRNA expression in ER+ breast cancer via mRNA stabilization and inhibition of p53 function.

The transcription factor 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 are 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 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 wildtype p53, SRC acted to overcome p53-mediated inhibition of estrogen-stimulated cell cycle entry and progression. SRC thus promotes cell proliferation in two ways: stabilizing MYC mRNA and 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.