DIFFERENTIAL EXPRESSION OF ALTERNATIVELY SPLICED C-ERBB-2 MESSENGER-RNA IN PRIMARY TUMORS, LYMPH-NODE METASTASES, AND BONE-MARROW MICROMETASTASES FROM BREAST-CANCER PATIENTS

We established an RT-PCR method to measure the amount of a 2.3-kb alte rnatively spliced mRNA of the human c-erbB-2/HER-2 proto-oncogene rela tive to the 4.6-kb fall-length transcript. For the first time, we demo nstrated production of c-erbB-2 extracellular domains via alternative splicing in breast cancer tissues, lymph node and bone marrow micromet astases. In 15 c-crbB-2-positive primary breast tumor samples, we foun d two significantly distinct subgroups: 6/15 had a low level of the ex tracellular fragment, and 9/15 showed an average 4.4-fold higher amoun t of the alternatively spliced mRNA Additionally, six lymph nodes and six bone marrow aspirates from metastatic breast cancer patients were analyzed: 5/6 lymph nodes and 6/6 bone marrow aspirates were found to produce elevated relative amounts of the truncated fragment. The resul ts demonstrate that our method is suitable for sensitive detection of c-erbB-2-positive micrometastasis and strongly suggest that the altern atively spliced c-erbB-2 variant is involved in the development of mic rometastasis in breast cancer. (C) 1998 Academic Press.