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A Novel RING-Type Ubiquitin Ligase Breast Cancer-Associated Gene 2 Correlates with Outcome in Invasive Breast Cancer

Laboratories of ¹ Molecular Pathology and ² Immunopathology, Department of Anatomic Pathology; ³ Division of Molecular and Cellular Biology; ⁴ Centre for Research in Women's Health, Sunnybrook and Women's College Health Sciences Centre; ⁵ Department of Laboratory Medicine and Pathobiology, Canadian Institutes of Health Research Group in Matrix Dynamics, University of Toronto, Toronto, Ontario, Canada; and ⁶ Regulation of Cell Growth Laboratory, Center for Cancer Research, National Cancer Institute at Frederick, NIH, Frederick, Maryland

Requests for reprints: Arun K. Seth, Laboratory of Molecular Pathology, Department of Anatomic Pathology, Sunnybrook and Women's College Health Sciences Center, Room E423a, 2075 Bayview Avenue, Toronto, ON, Canada M4N 3M5. Phone: 416-480-6100, ext. 7974; Fax: 416-480-4375; E-mail: arun.seth{at}utoronto.ca.

The RING finger family of proteins possess ubiquitin ligase activity and play pivotal roles in protein degradation and receptor-mediated endocytosis. In this study, we examined whether the breast cancer-associated gene 2 (BCA2), a novel RING domain protein, has E3 ubiquitin ligase activity and investigated its expression status in breast tumors. The full-length BCA2 gene was cloned from the human breast cancer cell line MDA-MB-468. It encodes an open reading frame of 304 amino acids and contains a RING-H2 domain. BCA2 maps to chromosome 1q21.1, a region known to harbor cytogenetic aberrations in breast cancers. We found that the BCA2 protein has an intrinsic autoubiquitination activity, the hallmark of E3 ligases, whereas mutant RING protein is not autoubiquitinated. This indicates that the BCA2 ubiquitin ligase activity is dependent on the RING-H2 domain. Using tissue microarrays and immunohistochemistry, we found strong to intermediate BCA2 staining in 56% of 945 invasive breast cancers cases, which was significantly correlated with positive estrogen receptor status [odds ratio (OR), 1.51; P = 0.004], negative lymph node status (OR, 0.73; P = 0.02), and an increase in disease-free survival for regional recurrence (OR, 0.45; P = 0.03). Overexpression of BCA2 increased proliferation and small interfering RNA inhibited growth of T47D human breast cancer cells and NIH3T3 mouse cells. The autoubiquitination activity of BCA2 indicates that it is a novel RING-type E3 ligase. Its association with clinical measures and its effects on cell growth indicate that BCA2 may be important for the ubiquitin modification of proteins crucial to breast carcinogenesis and growth.

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