In a series of 87 primary breast tumors, somatostatin receptor (SSR) expression was detected by in vitro autoradiography in 58 tumors. In 41 tumors the SSR expression was homogeneous and in 17 it was heterogeneous. Although the tumors were not selected by the investigators upon entry in the study, examination of the tumor and patient characteristics showed that a pre-selection had taken place for small tumors. Eighty percent of the tumors were classified as stage pT1 or pT2 tumors. This small tumor size and the large size of the tumor sections used for autoradiography can explain the high incidence of somatostatin expression in our series. Forty-three of these tumors, 30 SSR-positive and 13 SSR-negative, were tested for morphological and (immuno)histochemical markers of neuroendocrine differentiation. Three SSR-positive tumors were also positive for 2 or more other markers of neuroendocrine differentiation, suggesting that neuroendocrine breast tumors and SSR-positive breast tumors are overlapping, but independent, subgroups of tumors. To test whether specific genetic alterations are associated with SSR-positive or SSR-negative breast tumors, we examined in a selected series of 47 SSR-positive and 32 SSR-negative breast tumors a number of known genetic markers by Southern blotting. Deletions or rearrangements of the retinoblastoma (RB) tumor-suppressor gene were observed in 5 SSR-positive and 5 SSR-negative tumors. In 4 SSR-positive and also in 4 SSR-negative tumors an amplification of the neu oncogene was observed. Amplifications of the int-2 oncogene were found in 2 SSR-positive and 1 SSR-negative breast tumor. In one SSR-positive tumor an amplification of the c-myc oncogene was observed and in another SSR-positive tumor a rearrangement of the L-myc oncogene was found.