Disparate E-cadherin mutations in LCIS and associated invasive breast carcinomas

Abstract

Aims: The relation between lobular carcinoma in situ (LCIS) and invasive breast cancer is unresolved. In an attempt to establish whether LCIS is a precursor of invasive cancer the mutational status and the expression of E-cadherin was analysed in LCIS and associated invasive breast carcinoma in 23 patients.

Methods: Foci of LCIS and associated invasive carcinoma were individually microdissected from tissue from 23 patients. Exons 4-16 of the E-cadherin gene were analysed using single strand conformation polymorphism (SSCP); protein expression and the localisation of E-cadherin and beta-catenin were assessed with the use of immunohistochemistry.

Results: Immunohistochemistry revealed a lack of expression of E-cadherin and beta-catenin in most LCIS samples and invasive foci. In all but four cases, the staining pattern was identical in the LCIS and associated invasive areas. When E-cadherin was absent, beta-catenin was also undetected, suggesting a lack of expression of alternative classic cadherin members in these lesions. Coincident E-cadherin mutations in LCIS and associated invasive carcinoma were not identified in this series of patients. However, mutational analysis of E-cadherin in multiple foci of carcinoma in situ surrounding an invasive lesion provided evidence to support ductal carcinoma in situ as a precursor of invasive ductal carcinoma.

Conclusion: These data support the hypothesis that LCIS is not a precursor of invasive breast carcinoma but a marker of increased risk of developing invasive disease.

Figure 1

Lobular carcinoma in situ lesion (A) before and (B) after microdissection.

Figure 2

(A) Immunohistochemical staining of breast tissue showing the membranous location of E-cadherin in normal glands adjacent to carcinoma in situ (CIS) where no staining was found. (B) Immunostaining in a CIS lesion showing β-catenin localised to myoepithelial cells. No β-catenin was detected in cells of the CIS lesion, which also displayed loss of E-cadherin expression.

Figure 3

A single section from patient 22 showing the localisation of different microdissected lesions relative to the invasive carcinoma (focus 13). Foci 1, 2, 5, 11, and 12 were identified as ductal carcinoma in situ (DCIS); foci 3, 6, and 8 were identified as lobular carcinoma in situ (LCIS) and foci 4, 7, 9, and 10 were identified as intermediate morphology. Focus 13 represents an area of infiltrating ductal carcinoma.

Figure 4

Single strand conformation polymorphism analysis of exon 6 of the E-cadherin gene from patient 22. Lane 1, negative control; lanes 2 and 15, infiltrating ductal carcinoma focus 13; lanes 3–14, foci 1–12, respectively. Note the aberrantly migrating band in lanes 2, 3, 7, 9, 12, 14, and 15.