Dissociation of the E-Cadherin-Catenin-Complex (CCC) Is an Early and Progressive Event in Lobular Neoplasia.

Recent data suggests that some lobular carcinoma in situ (LCIS) lesions may behave as precursors to invasive lobular carcinoma (ILC). Loss of E-cadherin (E-CD) mediated cell adhesion is characteristic of both LCIS and ILC and is reflected in the dis-cohesive appearance of the individual cells. Subsequent dissociation of the intracellular E-cadherin-catenin-complex (CCC) facilitates tumor progression, invasion and migration. Whether disruption of the CCC plays a role in the progression of select LCIS lesions to ILC remains unclear. The aim of this study was to evaluate the relation between loss of E-CD and dissociation of the CCC in pure LCIS and LCIS with concurrent ILC (LCIS w/ILC). Methods Thirty patients undergoing mastectomy for LCIS alone or LCIS w/ ILC were prospectively enrolled to an IRB-approved protocol. FFPE blocks were retrieved and sections prepared for IHC. 18 cases had LCIS w/ ILC, 12 cases had pure-LCIS. IHC was performed for ER, PR, E-CD, N-cadherin (N-CD), and α-, β- and phospho-β-catenin. ER/PR positivity was scored as any nuclear staining, and E-CD and N-CD by any membranous staining. a- and β-catenin expression was scored by site (membranous/cytoplasmic/nuclear) of staining compared to normal. Dissociation of the CCC was defined by loss of membranous α- and β-catenin expression.Results Median age at surgery was 51yrs (range 40-79); patients with pure LCIS were younger than those with LCIS w/ ILC (median 48yrs vs 57yrs, p=.0002). Among 18 cases of LCIS w/ ILC, the median tumor size was 2cm (range 1.4-5.7), 9 patients had N1 disease and 1 had M1 disease. All pure LCIS, LCIS w/ ILC and ILC lesions were ER/PR positive and E-CD negative. N-CD expression was also absent in all pure LCIS, LCIS w/ ILC and ILC lesions. Normal α-catenin membranous expression was confirmed in all normal epithelial cells but decreased with the transition from in-situ to invasive disease: pure-LCIS lesions 83%; LCIS w/ ILC 28%; ILC 0%. Loss of membranous α-catenin expression was accompanied by cytoplasmic α-catenin expression in all lesions. A similar trend of decreasing membranous staining from in-situ to invasive disease was observed for β-catenin, however in contrast to α-catenin, cytoplasmic β-catenin expression decreased from 67% in pure LCIS to 11% in LCIS w/ ILC and 6% in ILC. Active β-catenin (nuclear staining) was not seen in pure LCIS lesions and was only present in one case of LCIS w/ ILC. Inactive (phospho) β-catenin expression was present in all lesions.Conclusion Loss of E-CD expression is an early event in lobular neoplasia however subsequent dissociation of the intracellular CCC a a ppears to be a progressive process with complete dissociation occurring only in invasive lesions. This finding suggests that complete disruption of the CCC may be required to facilitate maintenance of the invasive phenotype; however, the absence of N-CD expression and predominance of inactive β-catenin in both in situ and invasive lesions suggests that alternate mechanisms are also required to mediate the pro-invasive effects of CCC dissociation. Further studies into the mechanisms of CCC dissociation and downstream events in lobular carcinoma are needed to define the role of this process in the transition from in-situ to invasive disease. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6149.