The claudin expression signature of BRCA1-deficient breast cancer.

Abstract

e22174 Background: Unraveling the biology of BRCA1 related breast cancers may help to improve early detection methods in mutation carriers and patient tailored therapy. Claudins constitute a family of integral membrane proteins, forming the backbone of tight junctions. Altered claudin expression has been linked to oncogenesis in several ways. Decreased cellular polarity increases nutrient and growth factor supply to the rapid expanding tumor cells and decreased intercellular attachments might increase metastatic potential. The discovery of a claudin-low intrinsic subtype of breast cancer has further increased the interest in claudin expression. This study searched for distinct claudin expression profiles that characterize BRCA1 related breast cancers. Methods: 40 BRCA1 related breast cancers and 40 age-matched sporadic breast cancers were immunohistochemically stained for claudin 3, claudin 4, claudin 6 and claudin 7. Cytoplasmic and membranous expression were scored. In addition, a score was given for the overall expression (cytoplasmic and membranous combined) in comparison to the surrounding normal breast tissue. Results: Distinct claudin expression profiles were observed in BRCA1 deficient breast cancers. The hereditary cases had significantly more overexpression of claudin 3, when compared to the tumor surrounding tissue (45.7% vs 17.9%, p=0.03). Membranous claudin 6 expression was seen in 28% in BRCA1 related, compared to only 2.9% in sporadic cases (p=0.007; OR 13.2 95% CI 1.50-116). Claudin 6 was also more often overexpressed, when compared to the normal surrounding tissue in BRCA1 cases (62.5% vs. 19.4%). For claudin 7 an interesting pattern was observed. Membranous expression was observed more often in sporadic (80.0%) than hereditary (42.0%) carcinomas (p=0.001; OR 0.19 95% CI 0.07-0.50), whereas cytoplasmic expression was more abundant in BRCA1 related tumors (85.0% vs. 66.7%; p=0.06; OR 2.83 95% CI 0.95-8.46). Conclusions: Distinct claudin expression profiles characterize breast cancer in BRCA1 mutation carriers. Therefore, claudins may serve as biomarkers for diagnosis of BRCA1 related breast cancer. The mechanism of cytoplasmic relocalization of claudin 7 in BRCA1 deficient tumors deserves to be further studied.