Loss of expression of the
intercellular adhesion molecule E-cadherin frequently occurs in invasive lobular
breast carcinomas as a result of mutational inactivation. Expression patterns of
E-cadherin and the molecules comprising the cytoplasmic complex of adherens junctions, alpha-, beta- and
gamma-catenin, were studied in a series of 38 lobular
breast carcinomas with known
E-cadherin mutation status. The effect of loss of
E-cadherin by mutational inactivation (or other mechanisms) on the expression of
catenins was investigated. Complete loss of plasma membrane-associated
E-cadherin expression was observed in 32 out of 38 invasive
lobular carcinomas, for which in 21 cases a mutation was found in the extracellular domain of
E-cadherin. In total, 15 frameshift mutations of small deletions or insertions, ranging from 1 to 41 bp, three non-sense mutations, and three splice mutations were identified. Mutations were scattered over the whole coding region and no hot spots could be detected. In all cases, simultaneous loss of
E-cadherin and alpha- and
beta-catenin expression was found; in 50 per cent of these cases, additional loss of
gamma-catenin was observed. In six invasive
lobular carcinomas, expression of both
E-cadherin and
catenins was retained. In none of these
carcinomas was an
E-cadherin mutation detected.
Lobular carcinoma in situ adjacent to invasive
lobular carcinoma showed simultaneous loss of
E-cadherin and
catenins in all the cases studied--remarkably, also, in four cases positive for
E-cadherin and
catenin expression in the invasive component. These results indicate that simultaneous loss of
E-cadherin and alpha-, beta- and
gamma-catenin may be an important step in the formation of
lobular carcinoma in situ, as a precursor of invasive lobular
breast cancer. Events additional to
E-cadherin inactivation must be involved in the transition of
lobular carcinoma in situ to invasive
lobular carcinoma.