Abstract
An emerging paradigm holds that loss of negative signalling to receptor tyrosine kinases (RTKs) is permissive for their oncogenic activity. Herein, we have addressed tumor suppression by RALT/MIG-6, a transcriptionally controlled feedback inhibitor of ErbB RTKs, in breast cancer cells. Knockdown of RALT expression by RNAi enhanced the EGF-dependent proliferation of normal breast epithelial cells, indicating that loss of RALT signalling in breast epithelium may represent an advantageous condition during ErbB-driven tumorigenesis. Although mutational inactivation of the RALT gene was not detected in human breast carcinomas, RALT mRNA and protein expression was strongly and selectively reduced in ERBB2-amplified breast cancer cell lines. Reconstitution of RALT expression in ERBB2-amplified SKBr-3 and BT474 cells inhibited ErbB-2-dependent mitogenic signalling and counteracted the ability of ErbB ligands to promote resistance to the ErbB-2-targeting drug Herceptin. Thus, loss of RALT expression cooperates with ERBB2 gene amplification to drive full oncogenic signalling by the ErbB-2 receptor. Moreover, loss of RALT signalling may adversely affect tumor responses to ErbB-2-targeting agents.
| Original language | English |
|---|---|
| Pages (from-to) | 4540-4548 |
| Number of pages | 9 |
| Journal | Oncogene |
| Volume | 24 |
| Issue number | 28 |
| DOIs | |
| Publication status | Published - Jun 30 2005 |
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Keywords
- Breast cancer
- ErbB-2
- Herceptin
- MIG-6
- RALT
- Targeted therapies
ASJC Scopus subject areas
- Molecular Biology
- Cancer Research
- Genetics
Cite this
Loss of RALT/MIG-6 expression in ERBB2-amplified breast carcinomas enhances ErbB-2 oncogenic potency and favors resistance to Herceptin. / Anastasi, Sergio; Sala, Gianluca; Huiping, Chen; Caprini, Elisabetta; Russo, Giandomenico; Iacovelli, Stefano; Lucini, Fabiana; Ingvarsson, Sigurdur; Segatto, Oreste.
In: Oncogene, Vol. 24, No. 28, 30.06.2005, p. 4540-4548.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Loss of RALT/MIG-6 expression in ERBB2-amplified breast carcinomas enhances ErbB-2 oncogenic potency and favors resistance to Herceptin
AU - Anastasi, Sergio
AU - Sala, Gianluca
AU - Huiping, Chen
AU - Caprini, Elisabetta
AU - Russo, Giandomenico
AU - Iacovelli, Stefano
AU - Lucini, Fabiana
AU - Ingvarsson, Sigurdur
AU - Segatto, Oreste
PY - 2005/6/30
Y1 - 2005/6/30
N2 - An emerging paradigm holds that loss of negative signalling to receptor tyrosine kinases (RTKs) is permissive for their oncogenic activity. Herein, we have addressed tumor suppression by RALT/MIG-6, a transcriptionally controlled feedback inhibitor of ErbB RTKs, in breast cancer cells. Knockdown of RALT expression by RNAi enhanced the EGF-dependent proliferation of normal breast epithelial cells, indicating that loss of RALT signalling in breast epithelium may represent an advantageous condition during ErbB-driven tumorigenesis. Although mutational inactivation of the RALT gene was not detected in human breast carcinomas, RALT mRNA and protein expression was strongly and selectively reduced in ERBB2-amplified breast cancer cell lines. Reconstitution of RALT expression in ERBB2-amplified SKBr-3 and BT474 cells inhibited ErbB-2-dependent mitogenic signalling and counteracted the ability of ErbB ligands to promote resistance to the ErbB-2-targeting drug Herceptin. Thus, loss of RALT expression cooperates with ERBB2 gene amplification to drive full oncogenic signalling by the ErbB-2 receptor. Moreover, loss of RALT signalling may adversely affect tumor responses to ErbB-2-targeting agents.
AB - An emerging paradigm holds that loss of negative signalling to receptor tyrosine kinases (RTKs) is permissive for their oncogenic activity. Herein, we have addressed tumor suppression by RALT/MIG-6, a transcriptionally controlled feedback inhibitor of ErbB RTKs, in breast cancer cells. Knockdown of RALT expression by RNAi enhanced the EGF-dependent proliferation of normal breast epithelial cells, indicating that loss of RALT signalling in breast epithelium may represent an advantageous condition during ErbB-driven tumorigenesis. Although mutational inactivation of the RALT gene was not detected in human breast carcinomas, RALT mRNA and protein expression was strongly and selectively reduced in ERBB2-amplified breast cancer cell lines. Reconstitution of RALT expression in ERBB2-amplified SKBr-3 and BT474 cells inhibited ErbB-2-dependent mitogenic signalling and counteracted the ability of ErbB ligands to promote resistance to the ErbB-2-targeting drug Herceptin. Thus, loss of RALT expression cooperates with ERBB2 gene amplification to drive full oncogenic signalling by the ErbB-2 receptor. Moreover, loss of RALT signalling may adversely affect tumor responses to ErbB-2-targeting agents.
KW - Breast cancer
KW - ErbB-2
KW - Herceptin
KW - MIG-6
KW - RALT
KW - Targeted therapies
UR - http://www.scopus.com/inward/record.url?scp=22744445536&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=22744445536&partnerID=8YFLogxK
U2 - 10.1038/sj.onc.1208658
DO - 10.1038/sj.onc.1208658
M3 - Article
VL - 24
SP - 4540
EP - 4548
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 28
ER -