Breast Surgery International (BSI) was formed in 1999 as an integrated society within the International Surgical Society ISS/SIC. One goal is to promote breast surgery world wide and focus on the situation in the developing countries. An edited summary of a symposium on locally advanced breast cancer (LABC) and the current situation in two African countries and in Malaysia is reported. Diagnosis, management and treatment options differ from recommendations that prevail due to lack of resources, lack of access to facilities and cultural and socioeconomic barriers. Younger age at onset, more men are affected and locally advanced breast cancer dominates the clinical panorama. A rational treatment plan for LABC should have chemotherapy, surgery, radiotherapy and hormonal therapy as armaments. A unique opportunity exists for international interchange within a professional organization such as BSI, for providing training opportunities, for clinical and experimental studies of the world' s most common female malignancy.
AGR2 is an oncogenic endoplasmic reticulum (ER)-resident protein disulfide isomerase. AGR2 protein has a relatively unique property for a chaperone in that it can bind sequence-specifically to a specific peptide motif (TTIYY). A synthetic TTIYY-containing peptide column was used to affinity-purify AGR2 from crude lysates highlighting peptide selectivity in complex mixtures. Hydrogen-deuterium exchange mass spectrometry localized the dominant region in AGR2 that interacts with the TTIYY peptide to within a structural loop from amino acids 131-135 (VDPSL). A peptide binding site consensus of Tx[IL][YF][YF] was developed for AGR2 by measuring its activity against a mutant peptide library. Screening the human proteome for proteins harboring this motif revealed an enrichment in transmembrane proteins and we focused on validating EpCAM as a potential AGR2-interacting protein. AGR2 and EpCAM proteins formed a dose-dependent protein-protein interaction in vitro Proximity ligation assays demonstrated that endogenous AGR2 and EpCAM protein associate in cells. Introducing a single alanine mutation in EpCAM at Tyr251 attenuated its binding to AGR2 in vitro and in cells. Hydrogen-deuterium exchange mass spectrometry was used to identify a stable binding site for AGR2 on EpCAM, adjacent to the TLIYY motif and surrounding EpCAM's detergent binding site. These data define a dominant site on AGR2 that mediates its specific peptide-binding function. EpCAM forms a model client protein for AGR2 to study how an ER-resident chaperone can dock specifically to a peptide motif and regulate the trafficking a protein destined for the secretory pathway.