Transcriptional networks in neuroblastoma and breast cancer

Abstract

Transcription factors of the basic Helix-loop-helix (bHLH) family of proteins are important regulators of cellular processes such as proliferation and differentiation. Many cancer diseases show a block in differentiation, and aberrant regulation of several bHLH factors have been implicated in the development of different malignancies.



Neuroblastoma is a childhood tumour that arises in the developing sympathetic nervous system. The cells are blocked at an early stage of differentiation and display an immature phenotype. HEN1 is a bHLH transcription factor important for neuronal development originally isolated from neuroblastoma. We studied HEN1 and its functional interaction with the Lim-only (LMO) proteins in neuroblastoma. We detected a strong interaction between HEN1 and LMO4, and this interaction modulated the HEN1 transcription activity. Furthermore, we found a possible role for HEN1 in neuronal differentiation, however, the significance of this finding needs further experiments.



The O/E-protein family also share the HLH motif and functions in neuronal development. In our study on O/E-proteins, we discovered expression of these factors in neuroblastoma. We found that O/E-1 regulate the expression of the important neuronal marker genes SCG10 and Chromogranin A.



bHLH factors are also involved in the regulation of proper development of breast tissue. ID2 has been implicated in the development of breast cancer. We studied the ID2 expression in a breast cancer tissue array, where ID2 correlated with a less aggressive tumour phenotype.



Furthermore, we studied the relation between the important signalling pathways involving Notch1 and its target gene and ERK1/2 in breast cancer. The results revealed a Notch1-independent regulation of Hes1 and that ERK1/2 signalling might contribute to regulation of Hes1 expression in breast cancer.

• author: Manetopoulos, Christina
• supervisor: Håkan Axelson
• opponent: Professor Åman, Pierre, Department of Pathology, Gothenburg University, Sahlgrenska University Hospital, Sweden
• organization: Department of Translational Medicine
• publishing date: 2007
• type: Thesis
• publication status: published
• subject: Clinical Medicine
• keywords: Medicin (människa och djur), Medicine (human and vertebrates), basic helix-loop-helix, Neuroblastoma, Breast cancer
• in: Lund University Faculty of Medicine Doctoral Dissertation Series
• volume: 2007:4
• pages: 102 pages
• defense location: Entrance 78, 2nd floor, Pathology lecture hall University Hospital MAS, Malmö
• defense date: 2007-01-18 09:15:00
• ISSN: 1652-8220
• ISBN: 91-85559-74-1
• language: English
• LU publication?: yes
• additional info: C Manetopoulos, A Hansson, J Karlsson, J.I Jönsson and H Axelson. 2003. The Lim-only protein LMO4 modulates the transcriptional activity of HEN1. Biochem Biophys Res Commun., vol 307 pp 891-9.; P Persson, C Manetopoulos, J Nygren, R Gisler, H Axelson and M Sigvardson. 2004. Olf/EBF Proteins are Expressed in Neuroblastoma Cells: Potential Regulators of the Chromogranin A and SCG10 Promoters. Int J Cancer, vol 110 pp 22-30.; . 2005. High ID2 protein expression correlates with a favourable prognosis in patients with primary breast cancer and reduces cellular invasiveness of breast cancer cells. Int J Cancer, vol 115 pp 403-411.; M Stighall, C Manetopoulos, H Axelson and G Landberg. 2005. High ID2 protein expression correlates with a favourable prognosis in patients with primary breast cancer and reduces cellular invasiveness of breast cancer cells. Int J Cancer, vol 115 pp 403-411.; C Manetopoulos, S Svensson Månsson, M Johansson, G Landberg and H Axelson. . Association between the ERK pathway and the Notch target gene Hes1 in primary breast cancer and in breast cancer cell lines. (submitted)
• id: 6c38a779-673e-4399-b312-9e4b3b6f162e (old id 547842)
• date added to LUP: 2016-04-01 16:27:37
• date last changed: 2019-05-21 22:16:45