Relationship between p53 and p27 expression following HER2 signaling.

HER2, frequently associated with low p27 expression in breast tumors, when activated has been found to upmodulate p53 in tumor cells. The aim of this work was to investigate the role of p53 in the connection between HER2 and p27. Fifty-two breast tumor specimens, characterized for p53 mutations, were analyzed immunohistochemically (IHC) for HER2, p53 and p27 expression. p27, inversely associated with HER2, was found in 29% of tumors with IHC-negative mutated p53 versus 93% of tumors with accumulation of p53 protein and 59% with wild-type p53 (p=0.001), indicating a direct association between p53 and p27 expression. HER2-overexpressing cell lines carrying wild-type or null p53 protein, and treated with heregulin beta1 (HRG), were analyzed for expression and subcellular localization of p53 and p27. In HER2-overexpressing cells stimulated with HRG, p27 protein expression increased in parallel with p53 with no corresponding increase in p27 transcript. No p27 increase was observed in p53-null cells. Transfection with wild-type p53 restored p27 upmodulation in HRG-stimulated cells, indicating a crucial role of p53 in determining p27 upmodulation following HER2 activation. Together, our data demonstrate the crucial role of p53 in determining p27 upmodulation following HER2 activation. This could have implications in the response to Transtuzumab therapy.