| Title: |
Effects of HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) on NEU/HER2 overexpressing mammary tumours in MMTV-NEU-NT mice monitored by Magnetic Resonance Spectroscopy |
| Authors: |
Rodrigues Loreta M; Chung Yuen-Li; Al Saffar Nada M S; Sharp Swee Y; Jackson Laura E; Banerji Udai; Stubbs Marion; Leach Martin O; Griffiths John R; Workman Paul |
| Source: |
BMC Research Notes, Vol 5, Iss 1, p 250 (2012) |
| Publisher Information: |
BMC |
| Publication Year: |
2012 |
| Collection: |
Directory of Open Access Journals: DOAJ Articles |
| Subject Terms: |
Magnetic resonance spectroscopy; MMTV-NEU-NT tumours; ERBB2/ HER2/ NEU; HSP90; 17-AAG; Medicine; Biology (General); QH301-705.5; Science (General); Q1-390 |
| Description: |
Background The importance of ERBB2/NEU/HER2 in the response of breast tumours to the heat shock protein 90 (HSP90) inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG; tanespimycin) has been demonstrated in the clinic. ERBB2 is an oncoprotein client that is highly dependent on HSP90. This and other oncogenic client proteins (e.g. B-RAF, C-RAF, ALK and CDK4) are depleted by 17-AAG in both animal tumours and patients. Here we investigate by Magnetic Resonance Spectroscopy (MRS) the metabolic response of 17-AAG in spontaneous, NEU/HER2 driven mammary tumours in transgenic MMTV-NEU-NT mice and in cells isolated and cultured from these tumours. Methods Mammary tumours were monitored by 31 P MRS in vivo and in tumour extracts, comparing control and 17-AAG treated mice. A cell line derived from NEU/HER2 mammary tumours was also cultured and the effect of 17-AAG was measured by 31 P MRS in cell extracts. Molecular biomarkers were assessed by immunoblotting in extracts from cells and tumours. For comparison of tumour volume, metabolite concentrations and Western blot band intensities, two-tailed unpaired t-tests were used. Results The NEU/HER2 mammary tumours were very sensitive to 17-AAG and responded in a dose-dependent manner to 3 daily doses of 20, 40 and 80mg/kg of 17-AAG, all of which caused significant regression. At the higher doses, 31 P MRS of tumour extracts showed significant decreases in phosphocholine (PC) and phosphoethanolamine (PE) whereas no significant changes were seen at the 20mg/kg dose. Extracts of isolated cells cultured from the mammary carcinomas showed a significant decrease in viable cell number and total PME after 17-AAG treatment. Western blots confirmed the expected action of 17-AAG in inducing HSP72 and significantly depleting HSP90 client proteins, including NEU/HER2 both in tumours and in isolated cells. Conclusions The data demonstrate the high degree of sensitivity of this clinically relevant NEU/HER2-driven tumour model to HSP90 inhibition by 17-AAG, consistent with the ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
http://www.biomedcentral.com/1756-0500/5/250; https://doaj.org/toc/1756-0500; https://doaj.org/article/fd9496f4b922426fa97e6e98105258a7 |
| DOI: |
10.1186/1756-0500-5-250 |
| Availability: |
https://doi.org/10.1186/1756-0500-5-250; https://doaj.org/article/fd9496f4b922426fa97e6e98105258a7 |
| Accession Number: |
edsbas.BE238F58 |
| Database: |
BASE |