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Inefficient proteasomal‐degradation pathway stabilizes AP‐2α and activates HER‐2/ neu gene in breast cancer
Author(s) -
Li Min,
Wang Yingqun,
Hung MienChie,
Kannan Perry
Publication year - 2005
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.21426
Subject(s) - cancer research , cell culture , oncogene , biology , carcinogenesis , gene expression , downregulation and upregulation , microbiology and biotechnology , proteasome , messenger rna , cell , cancer , gene , cell cycle , genetics
HER ‐ 2 /neu proto‐oncogene is overexpressed in about one fourth of human breast cancers. AP‐2 transcription factors bind to the HER ‐2/neu gene promoter and activate its expression. In a striking concurrence, anomalous abundance of AP‐2α protein or its homolog AP‐2γ is also detected with HER‐2/ neu protein in mammary tumor‐derived cell lines. This suggests that the deregulation of AP‐2 is the preceding pathogenic event and probably the pivotal one in this type of mammary carcinogenesis. We examined the process of AP‐2α gene expression in mammary carcinoma cell lines to identify where the aberration had occurred. We found no amplification of the AP‐2α gene. Its promoter was marginally upregulated; however, it did not significantly increase the mRNA levels. When the AP‐2α protein was examined, a remarkable stability was seen in breast cancer cell lines MDA‐MB‐453 and SK‐BR‐3, with a half‐life of over 30 hr. This is sharply higher than the approximate 1 hr observed in mammary epithelial cell line MCF‐10A and murine cell line NIH 3T3. Treatment of MCF‐10A and NIH 3T3 cells with the proteasome inhibitor MG‐132 showed that AP‐2α was ubiquitinated and its level significantly increased. Moreover, this increase was accompanied by elevated levels HER‐2/neu protein. In contrast, weaker ubiquitination of AP‐2α was seen in MDA‐MB‐453 and SK‐BR‐3 cancer cells, and MG‐132 treatment did not raise the AP‐2α level any further. These results uncover that unusual stability is the main mechanism that raises the levels of AP‐2 proteins, and in addition, provide the first clue that defective ubiquitin‐dependent proteasomal‐degradation pathway is possibly the prime cause that affects the HER‐2 /neu gene and culminates in breast cancer. © 2005 Wiley‐Liss, Inc.