BRCA1 deficiency leads to aberrant epithelial differentiation in the thymus.

Abstract

BRCA1 (breast cancer 1, early onset) is originally identified as a tumor suppressor in hereditary breast and ovarian cancer. Recent studies have suggested that BRCA1 contributes to the cell fate decisions in mammary epithelium. Although BRCA1 has been shown to be expressed in the thymus, its physiologic role(s) in the thymus remain unclear. In this study, we found that BRCA1 was expressed in a subset of thymic medullary epithelial cells: epithelial cell adhesion molecule (EpCAM, CD326) positive, UEA-1 ligand positive, and Aire negative. To clarify its functional significance, we analyzed the differentiation of thymic epithelial cells in mice in which BRCA1 was specifically deleted in K14-expressing cells. Interestingly, conditional BRCA1-deficient mice displayed enhanced development of Hassall's corpuscles. Notably, thymoproteasome catalytic subunit β5t (proteasome subunit beta 11), a marker of cortical thymic epithelial cells (cTECs), was frequently detected adjacent to Hassall's corpuscles in BRCA1 knockout mice. In addition, medullary β5t+ cells appeared to differentiate into cTECs. In addition, BRCA1 deficiency led to increased generation of regulatory T cells. Thus, BRCA1 was also found to regulate epithelial differentiation in the thymus. Our observations in BRCA1-deficient mice may be relevant to understanding the immune system in human with BRCA1 germline mutations.