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Open Access Research article

Negative transcriptional control of ERBB2 gene by MBP-1 and HDAC1: diagnostic implications in breast cancer

Flavia Contino1, Claudia Mazzarella1, Arianna Ferro1, Mariavera Lo Presti13, Elena Roz3, Carmelo Lupo3, Giovanni Perconti2, Agata Giallongo2* and Salvatore Feo12*

Author Affiliations

1 Dipartimento di Scienze e Tecnologie Molecolari e Biomolecolari, Università di Palermo, Viale delle Scienze, Ed. 16, Palermo I-90128, Italy

2 Istituto di Biomedicina e Immunologia Molecolare, CNR, Via Ugo La Malfa, 153, Palermo I-90146, Italy

3 Unità di Anatomia Patologica, Dipartimento Oncologico di III livello La Maddalena, Palermo, Italy

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BMC Cancer 2013, 13:81  doi:10.1186/1471-2407-13-81

Published: 19 February 2013

Abstract

Background

The human ERBB2 gene is frequently amplified in breast tumors, and its high expression is associated with poor prognosis. We previously reported a significant inverse correlation between Myc promoter-binding protein-1 (MBP-1) and ERBB2 expression in primary breast invasive ductal carcinoma (IDC). MBP-1 is a transcriptional repressor of the c-MYC gene that acts by binding to the P2 promoter; only one other direct target of MBP-1, the COX2 gene, has been identified so far.

Methods

To gain new insights into the functional relationship linking MBP-1 and ERBB2 in breast cancer, we have investigated the effects of MBP-1 expression on endogenous ERBB2 transcript and protein levels, as well as on transcription promoter activity, by transient-transfection of SKBr3 cells. Reporter gene and chromatin immunoprecipitation assays were used to dissect the ERBB2 promoter and identify functional MBP-1 target sequences. We also investigated the relative expression of MBP-1 and HDAC1 in IDC and normal breast tissues by immunoblot analysis and immunohistochemistry.

Results

Transfection experiments and chromatin immunoprecipitation assays in SKBr3 cells indicated that MBP-1 negatively regulates the ERBB2 gene by binding to a genomic region between nucleotide −514 and −262 of the proximal promoter; consistent with this, a concomitant recruitment of HDAC1 and loss of acetylated histone H4 was observed. In addition, we found high expression of MBP-1 and HDAC1 in normal tissues and a statistically significant inverse correlation with ErbB2 expression in the paired tumor samples.

Conclusions

Altogether, our in vitro and in vivo data indicate that the ERBB2 gene is a novel MBP-1 target, and immunohistochemistry analysis of primary tumors suggests that the concomitant high expression of MBP-1 and HDAC1 may be considered a diagnostic marker of cancer progression for breast IDC.

Keywords:
MBP-1; ERBB2; Transcriptional regulation; Histone Deacetylase; Breast cancer