Expression of the Brn-3b transcription factor correlates with expression of HSP-27 in breast cancer biopsies and is required for maximal activation of the HSP-27 promoter.

Abstract

In breast cancer, overexpression of the small heat shock protein, HSP-27, is associated with increased anchorage-independent growth, increased invasiveness, and resistance to chemotherapeutic drugs and is associated with poor prognosis and reduced disease-free survival. Therefore, factors that increase the expression of HSP-27 in breast cancer are likely to affect the prognosis and outcome of treatment. In this study, we show a strong correlation between elevated levels of the Brn-3b POU transcription factor and high levels of HSP-27 protein in manipulated MCF-7 breast cancer cells as well as in human breast biopsies. Conversely, HSP-27 is decreased on loss of Brn-3b. In cotransfection assays, Brn-3b can strongly transactivate the HSP-27 promoter, supporting a role for direct regulation of HSP-27 expression. Brn-3b also cooperates with the estrogen receptor (ER) to facilitate maximal stimulation of the HSP-27 promoter, with significantly enhanced activity of this promoter observed on coexpression of Brn-3b and ER compared with either alone. RNA interference and site-directed mutagenesis support the requirement for the Brn-3b binding site on the HSP-27 promoter, which facilitates maximal transactivation either alone or on interaction with the ER. Chromatin immunoprecipitation provides evidence for association of Brn-3b with the HSP-27 promoter in the intact cell. Thus, Brn-3b can, directly and indirectly (via interaction with the ER), activate HSP-27 expression, and this may represent one mechanism by which Brn-3b mediates its effects in breast cancer cells.

• Authors: Sonia A Lee, Daniel Ndisang, Chandrakant Patel, Jonathan H Dennis, David J Faulkes, Corrado D'Arrigo, Laila Samady, Saleha Farooqui-Kabir, Richard J Heads, David S Latchman, Vishwanie S Budhram-Mahadeo
• Journal: Cancer research (Cancer Res) Vol. 65 Issue 8 Pg. 3072-80 (Apr 15 2005) ISSN: 0008-5472 [Print] United States
• PMID: 15833836 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• HSP90 Heat-Shock Proteins
• Heat-Shock Proteins
• Receptors, Estrogen
• Transcription Factor Brn-3
• Transcription Factor Brn-3B
• Transcription Factors

Topics

• Base Sequence
• Biopsy
• Breast Neoplasms (genetics, metabolism, pathology)
• Cell Line, Tumor
• Chromatin Immunoprecipitation
• DNA-Binding Proteins (biosynthesis, genetics)
• Gene Expression Regulation, Neoplastic
• HSP90 Heat-Shock Proteins (biosynthesis, genetics)
• Heat-Shock Proteins (biosynthesis, genetics)
• Humans
• Molecular Sequence Data
• Mutagenesis, Site-Directed
• Promoter Regions, Genetic
• RNA Interference
• Receptors, Estrogen (biosynthesis, genetics)
• Transcription Factor Brn-3
• Transcription Factor Brn-3B
• Transcription Factors (biosynthesis, genetics)
• Transcriptional Activation
• Transfection