One of the recent puzzles in cancer research has been why the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 do not seem to be involved in sporadic cancer. Expression of BRCA1 is occasionally lost because of promoter hypermethylation, but the same has not been found for BRCA2. The discovery of the BRCA2-interacting protein EMSY, by Tony Kouzarides and colleagues, might now allow part of this puzzle to be solved. It is thought to provide the link between BRCA2 and sporadic cancer.

EMSY was identified in a yeast two-hybrid screen with the amino terminus of BRCA2 and the interaction was confirmed using purified proteins. The activities of BRCA2 include transcriptional activation, DNA repair and chromatin remodelling, and EMSY is implicated in all of these. It can repress the ability of BRCA2 to activate transcription of a reporter construct; it localizes to sites of DNA damage after γ-irradiation; and it interacts with chromatin-remodelling proteins.

The potential involvement in chromatin remodelling was discovered after EMSY was cloned. The sequence was novel, but contained an 80-amino-acid domain — named EMSY N-terminal domain (ENT) — that was found in nine Arabidopsis proteins. These proteins also contained a new Royal-family domain, designated Agenet, that can recognize lysine-methylated histones, which explains the link with chromatin remodelling.

As EMSY does not possess such a domain, might it, instead, interact with other proteins that do contain Royal-family domains? In two-hybrid screens with the N terminus of EMSY, over 80% of the interacting clones contained a Royal-family domain. The authors showed that two of these, HP1β and BS69, could also interact in vivo. So, it is likely that one of the functions of EMSY is in chromatin regulation.

But what about the connection with cancer? EMSY maps to chromosome 11q13.4-5, which is frequently amplified in sporadic breast cancer. Four different amplicons are found within this region and the authors used fluorescence in situ hybridization (FISH) to show that EMSY was amplified in 5/28 (18%) breast cancer cell lines and in 1/5 samples from newly diagnosed patients. The degree of amplification correlated with the expression level of EMSY and the authors showed that EMSY could be amplified independently from other genes in the region.

To investigate the significance of this amplification, the authors next looked at how it affects prognosis by comparing expression in tissue samples from patients with sporadic breast cancer with their outcome. EMSY was shown to be amplified in 70/551 (13%) cases and the median disease-specific survival for node-negative breast cancer was 6.4 years with the amplification, but 14 years without. So, EMSY amplification correlates with a poorer prognosis, specifically for node-negative breast cancer.

As BRCA2 mutation increases susceptibility to ovarian cancer, as well as to breast cancer, the authors investigated whether EMSY was amplified in sporadic ovarian cancer. They found amplification in 17% of high-grade carcinomas, but none in low-grade.

So, the BRCA2 pathway might be involved in sporadic breast and ovarian cancer after all. Although this is yet to be confirmed, the fact that EMSY and BRCA2 have overlapping functions and cause the same pathologies is encouraging. As EMSY inhibits the transcriptional activation function of BRCA2, it is certainly possible that BRCA2 deletion and EMSY amplification have similar effects.