Carcinogen inducibility in vivo and down-regulation of DMBT1 during breast carcinogenesis.

Deleted in malignant brain tumors 1 (DMBT1) has been proposed as a candidate tumor suppressor for brain and epithelial cancer. Initial studies suggested loss of expression rather than mutation as the predominant mode of DMBT1 inactivation. However, in situ studies in lung cancer demonstrated highly sophisticated changes of DMBT1 expression and localization, pointing to a chronological order of events. Here we report on the investigation of DMBT1 in breast cancer in order to test whether these principles might also be attributable to other tumor types. Comprehensive mutational analyses did not uncover unambiguous inactivating DMBT1 mutations in breast cancer. Expression analyses in the human and mouse mammary glands pointed to the necessity of DMBT1 induction. While age-dependent and hormonal effects could be ruled out, 9 of 10 mice showed induction of Dmbt1 expression after administration of the carcinogen 7,12-dimethybenz(alpha)anthracene prior to the onset of tumorigenesis or other histopathological changes. DMBT1 displayed significant up-regulation in human tumor-flanking tissues compared to in normal breast tissues (P < 0.05). However, the breast tumor cells displayed a switch from lumenal secretion to secretion to the extracellular matrix and a significant down-regulation compared to that in matched normal flanking tissues (P < 0.01). We concluded that loss of expression also is the predominant mode of DMBT1 inactivation in breast cancer. The dynamic behavior of DMBT1 in lung carcinoma is fully reflected in breast cancer, which suggests that this behavior might be common to tumor types arising from monolayered epithelia. Copyright 2003 Wiley-Liss, Inc.