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Growth Factor Regulation of a 26S Proteasomal Subunit in Breast Cancer

Authors' Affiliation: Department of Molecular & Cellular Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Rakesh Kumar, Department of Molecular & Cellular Oncology, University of Texas M. D. Anderson Cancer Center, Box 108, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-745-3558; Fax: 713-745-3792; E-mail: rkumar{at}mdanderson.org.

Purpose: We sought to gain insight into the mechanisms of heregulin-ß1 (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.

Key Words: Heregulin • HER2 • S4 • Rpt2 • Breast cancer

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