alternative tfap2a isoforms have distinct activities in breast cancer替代tfap2a亚型乳腺癌不同的活动.pdfVIP

Berlato et al. Breast Cancer Research 2011, 13:R23 /content/13/2/R23 RESEARCH ARTICLE Open Access Alternative TFAP2A isoforms have distinct activities in breast cancer * Chiara Berlato, KaYi V Chan, Anna M Price, Monica Canosa, Angelo G Scibetta and Helen C Hurst Abstract Introduction: AP-2a is a transcription factor implicated in the regulation of differentiation and proliferation in certain tissues, including the mammary gland. In breast tumours, continued expression of AP-2a has been correlated with a better prognosis, but this is hard to reconcile with a reported role in the upregulation of the ERBB2 oncogene. The existence of TFAP2A isoforms, deriving from alternative first exons and differing in their N- terminal sequence, has been described in some mammals, but their relative abundance and activity has not been investigated in the human breast. Methods: Expression levels of four TFAP2A isoforms were assayed at the level of RNA and protein (via the generation of isoform-specific antibodies) in a panel of breast tumour cell lines and in tissue from normal breast and primary tumour samples. Expression constructs for each isoform were used in reporter assays with synthetic and natural promoters (cyclin D3 and ERBB2) to compare the activation and repression activity of the isoforms. Results: We demonstrate that the two isoforms AP-2a 1b and AP-2a 1c, in addition to the originally cloned, AP- 2a 1a, are conserved throughout evolution in vertebrates. Moreover, we show that isoform 1c in particular is expressed at levels at least on a par with the 1a isoform in breast epithelial lines and tissues and may be more highly expressed in tamoxifen resistant tumours. The isoforms share a similar