Abstract
BackgroundHER2 over-expression is related with a poor prognosis in patients with invasive breast cancer tumors. Clinical associations have reported that somatic mutations of p53 more frequently detected in cases of sporadic breast cancer of the HER2 subtypes, besides a high percentage of HER2-amplifying tumors carry germline mutations of p53. The mechanisms responsible for the acquisition of oncogenic functions of p53 mutant proteins (mtp53), known as Gain of Function (GOF), over HER2 expression have not been reported. The objective of this study was to evaluate a possible relationship between p53 mutants and HER2 regulation.MethodsHER2 expression (transcription and protein), as well as HER2 protein stabilization have been evaluated after inducing or silencing of p53 mutants’ expression in cell lines. Finally, we evaluated the interaction of the p53 mutants over the HER2 receptor promoter.ResultsHigher HER2 expression in cell lines harboring endogenous mtp53 compared with wt or null expression of p53 cell lines. Transfection of p53 mutants (R248Q and R273C) in cell lines increased the expression of HER2. Silencing of p53 mutants, decrease HER2 expression. The p53 mutants R248Q and R273C significantly increase the luciferase activity on the HER2 promoter, and both mutants also promote acetylation of H3 and H4 histones binding in it.ConclusionsThese findings show for the first time that p53 mutants induce over-expression of HER2 at transcriptional level of the HER2 protein. Our results could have clinical implications in breast cancer and other types of cancer where HER2 is over-expressed and used as a therapy target.
Highlights
HER2 over-expression is related with a poor prognosis in patients with invasive breast cancer tumors
HER2 and p53 expression levels in cancer cell lines As a first approach to the correlation that may exist between p53 mutant proteins and the HER2 receptor expression, we evaluated the Messenger Ribonucleic acid (mRNA) and protein levels of p53 and HER2 in a panel of human cancer cells: MCF-7 and HeLa cells harboring wild-type p53, Saos-2 with null expression of p53 (p53-null), as well as, C33A, SKBR-3 and OVCAR-3 harboring three of the most frequent p53 hot-spot mutations (p53R273C, p53R175H and p53R248Q)
For HER2 mRNA expression, quantitative PCR (RT-qPCR) assays revealed that the cell lines harboring mutant p53 had higher expression levels when compared with the cell lines with wild-type or null p53 expression (Fig. 1a)
Summary
HER2 over-expression is related with a poor prognosis in patients with invasive breast cancer tumors. The mechanisms responsible for the acquisition of oncogenic functions of p53 mutant proteins (mtp53), known as Gain of Function (GOF), over HER2 expression have not been reported. Many of the GOF data come from p53-null systems where the expression levels of re-expressed mutant p53 were comparable to those observed in cancer cells. Elucidating the mechanism leading to HER2 gene up-regulation will be an important step to understand the pathogenesis of aggressive subset of tumors over-expressing HER2 [11], as well as to find novel alternatives for therapy. A larger study that supports this association, found that patients with breast cancer harboring a germline TP53 mutation, have significantly higher HER2 positive tumors prevalence, compared to their counterparts who lack any mutation [13]. Understanding the specific mechanisms for this relationship might reveal diagnostic and therapeutic insights in HER2 positive cancers
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