Ubiquitin Ligase Affects Breast Cancer Growth

Researchers have found that breast cancer patients whose tumor cells express high levels of breast cancer-associated gene 2 (BCA2) have a much better chance of surviving the disease than do patients with little or BCA2 activity.

BCA2 is a novel RING domain protein, which has E3 ubiquitin ligase activity. A ubiquitin ligase is a protein which covalently attaches ubiquitin to a lysine residue on a target protein. The ubiquitin ligase is typically involved in polyubiquitylation: a second ubiquitin is attached to the first, a third is attached to the second, and so forth. Polyubiquitylation marks proteins for degradation by the proteasome.

Ubiquitin ligase is referred to as an E3 and operates in conjunction with an E1 ubiquitin-activating enzyme and an E2 ubiquitin-conjugating enzyme. There is one major E1 enzyme, shared by all ubiquitin ligases, which uses ATP to activate ubiquitin for conjugation and transfers it to an E2 enzyme. The E2 enzyme interacts with a specific E3 partner and transfers the ubiquitin to the target protein. The E3, which may be a multi-protein complex, is generally responsible for targeting ubiquitylation to specific substrate proteins. An E3 recognizes its substrates based on the presence of a specific ubiquitination signal, and catalyzes the formation of an isopeptide bond between a substrate (or ubiquitin) lysine residue and the C terminus of ubiquitin. Recent findings have revealed that all known E3s utilize one of just two catalytic domains--a HECT domain or a RING finger--and crystal structures have provided the first detailed views of an active site of each type.

In the current study investigators at the University of Toronto (ON, Canada; www.utoronto.ca) cloned the full-length BCA2 gene from the human breast cancer cell line MDA-MB-468. The gene, which mapped to chromosome 1q21.1, encoded an open reading frame of 304 amino acids and contained a RING-H2 domain. They found that the BCA2 protein had an intrinsic autoubiquitination activity, whereas mutant RING protein was not autoubiquitinated.

They reported in their paper in the November 15, 2005, issue of Cancer Research that by using tissue microarrays and immunohistochemistry, it was possible to demonstrate strong-to-intermediate BCA2 staining in 56% of 945 invasive breast cancers cases. This result correlated significantly with positive estrogen receptor status, negative lymph node status, and an increase in disease-free survival for regional recurrence.

"Now that we have determined that higher levels of BCA2 are associated with a positive outcome, we are working to determine whether the BCA2 ligase functions as an oncogene in some tissues and as a tumor suppressor in others,” said senior author Dr. Arun Seth, professor of molecular and cellular biology at the University of Toronto. "Targeting the BCA2 mediated breakdown of tumor suppressors could provide a new therapy to block breast tumor growth.”



Related Links:
University of Toronto