Abstract
Abstract P-cadherin is a classical cadherin which has been extensively studied concerning its functions and its prognostic value in breast cancer. Moderate to intense expression of P-cadherin has been identified in 30% - 50% of invasive ductal carcinomas of the breast, being reported to be strongly associated with proliferative and high histological grade, decreased patient survival and as a marker of the aggressive behaviour of basal-like and HER-2 tumour subtypes. In vitro, P-cadherin overexpression is also able to induce increased cell invasion and migration. However, only a few works have been published in order to decipher the regulatory mechanisms behind P-cadherin overexpression in breast cancer. P-cadherin is up-regulated by the antiestrogen ICI 182,780, suggesting that the lack of ERalpha signalling may be responsible for the aberrant P-cadherin expression in breast cancer, but the mechanisms underlying this ICI-induced aggressive behaviour are completely unknown. The aim of this study was to determine whether the induction of the CDH3 gene is a direct effect of ICI 182,780 at CDH3 promoter level or would require the prior induction of other genes/proteins or epigenetic mechanisms. We found that ICI 182,780 increases CDH3 promoter activity as well as induces an epigenetic mechanism that lead to activating histone modifications at putative C/EBPbeta binding sites in at the CDH3 promoter. We also demonstrate that this transcription factor is able to directly activate P-cadherin transcription in breast cancer cells and that these two proteins are highly associated in human breast carcinomas, being both significantly related with high grade and proliferative invasive breast carcinomas. This study brings forward the characterization of putative intracellular pathways and epigenetic mechanisms that are able to induce P-cadherin overexpression in breast cancer cells and, in general, contribute to clarify the ability of ICI 182,780 to induce expression of signal transduction genes normally repressed by oestrogen/ER signalling. In addition, we showed for the first time that the transcription factor C/EBPbeta is able to regulate P-cadherin overexpression in breast cancer. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4981.
Published Version
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