To determine the developmental stages at which the highly malignant phenotype of breast carcinoma is acquired, the histological grade and c-erbB-2 oncoprotein expression status were examined for both the ductal carcinoma in situ (DCIS) and invasive components of 437 separate invasive breast carcinomas. In 218 invasive carcinomas with high-grade atypia (grade 3), the DCIS components were grade 2-3 in 158 cases (73%). Twenty-seven (12%) showed an obvious stepwise increase from grade 1 DCIS to grade 3 invasive carcinoma, and 25 of these tumors had DCIS components covering < 25% of their area. Ductal carcinoma in situ components were undetectable in 33 (15%) of invasive carcinomas. The incidence of c-erbB-2 overexpression was higher in grade 3 carcinomas with grade 2-3 DCIS components (55%, 80 of 146) than in those with grade 1 DCIS components (5%, one of 25). The incidence was also higher in grade 3 carcinomas with DCIS components covering > or =25% of the tumor area (71%, 39 of 55) than in those with DCIS over < 25% of the total area (36%, 42 of 116) or without DCIS components (6%, two of 33). There appeared to be three prototypic pathways to high-grade breast carcinoma: (i) invasion by a high-grade DCIS regardless of the extent of DCIS spread; (ii) invasion by a low-grade DCIS during the microscopic stages, accompanied by an obvious enhancement of the grade; and (iii) development of an invasive carcinoma ab initio. c-erbB-2 overexpression appeared to be frequently involved in the early development of the first group but showed little relation to the invasive process in any of these three pathways. The histological grade and c-erbB-2 overexpression appeared to be largely established during the early microscopic stages of a DCIS or invasive carcinoma.