TY - JOUR
T1 - Growth factor regulation of a 26S proteasomal subunit in breast cancer
AU - Barnes, Christopher J.
AU - Li, Feng
AU - Talukder, Amjad H.
AU - Kumar, Rakesh
PY - 2005/4/15
Y1 - 2005/4/15
N2 - Purpose: We sought to gain insight into the mechanisms of heregulin-β1 (HRG) action on breast epithelial cells by identifying and characterizing HRG-regulated proteins. Experimental Design: Differential display mRNA screening of human breast cancer cells grown in the presence or absence of HRG was used to identify HRG-regulated genes. Biochemical and functional studies were undertaken to examine the impact of HRG and the therapeutic antibody herceptin on protein expression, localization, and function. Results: We identified the ATPase subunit 4 (S4) of the 26S proteasome as a HRG-regulated target. Both S4 mRNA and protein levels were increased by HRG; however, this HRG-stimulated increase was blocked by the therapeutic antibody herceptin. S4 expression was significantly increased in primary human breast tumors and in estrogen receptor - negative tumors. Coimmunoprecipitation, immunofluorescence, and ATPase activity assays suggested that HRG also induced S4 activity and formation of a functional proteasome complex. Conclusions: This is the first demonstration of growth factor - regulated expression, localization, and activity of the S4 subunit of the 26S proteasome in human breast cancer cells. These findings now provide a potential mechanistic rationale for the use of proteasome inhibitors in breast cancers with active HRG signaling.
AB - Purpose: We sought to gain insight into the mechanisms of heregulin-β1 (HRG) action on breast epithelial cells by identifying and characterizing HRG-regulated proteins. Experimental Design: Differential display mRNA screening of human breast cancer cells grown in the presence or absence of HRG was used to identify HRG-regulated genes. Biochemical and functional studies were undertaken to examine the impact of HRG and the therapeutic antibody herceptin on protein expression, localization, and function. Results: We identified the ATPase subunit 4 (S4) of the 26S proteasome as a HRG-regulated target. Both S4 mRNA and protein levels were increased by HRG; however, this HRG-stimulated increase was blocked by the therapeutic antibody herceptin. S4 expression was significantly increased in primary human breast tumors and in estrogen receptor - negative tumors. Coimmunoprecipitation, immunofluorescence, and ATPase activity assays suggested that HRG also induced S4 activity and formation of a functional proteasome complex. Conclusions: This is the first demonstration of growth factor - regulated expression, localization, and activity of the S4 subunit of the 26S proteasome in human breast cancer cells. These findings now provide a potential mechanistic rationale for the use of proteasome inhibitors in breast cancers with active HRG signaling.
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U2 - 10.1158/1078-0432.CCR-04-1989
DO - 10.1158/1078-0432.CCR-04-1989
M3 - Article
C2 - 15837734
AN - SCOPUS:17144389347
SN - 1078-0432
VL - 11
SP - 2868
EP - 2874
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 8
ER -