Obscurins Invade Breast Cancer Research

Obscurins are giant multidomain proteins, encoded by the single OBSCN gene, which play important roles in the structural organization and contractile activity of striated muscles. Recently, genetic linkage analysis identified OBSCN and TP53 as the only common and most frequently mutated genes in breast and colorectal cancers among 13,023 genes studied. Our laboratory set forth to study the expression profile of the OBSCN gene in breast cancer. Our data revealed that obscurins are readily expressed in normal breast epithelial cells (MCF10A), but their amounts are significantly diminished in breast cancer cells (MCF7 & MDA‐MB‐ 231). Down‐regulation of obscurins in MCF10A cells via siRNA technology resulted in decreased levels of β‐catenin and Ecadherin, both of which are major components of adherens junctions (AJ) and are heavily implicated in the formation and metastasis of breast tumors. Residual β‐catenin showed a preferential nuclear accumulation in obscurin‐null MCF10A cells, and a concomitant loss from cell‐cell junctions. Interestingly, TGF‐β1 treatment of normal MCF10A cells resulted in down‐regulation of obscurins, β‐catenin, and E‐cadherin. In summary, our findings indicate that TGF‐β1 may negatively regulate the expression of obscurins in breast epithelium, loss of which results in diminished levels and altered distribution of major AJ proteins, and thus disruption of cell‐cell contacts.