We have previously shown that thrombospondin (TSP) is present in normal breast secretions, and high levels of TSP are observed in malignant breast secretions and cytosols. Three genes encoding for three distinct TSPs (TSP1, TSP2, TSP3) have recently been described. In this study, using both immunohistochemistry and in situ hybridization, we report on the distribution of TSP1 in normal, hyperplastic, and neoplastic human breast. Its immunolocalization was also compared with that of two known cell surface receptors for TSP1: CD36 and CD51. In nonlactating ducts of normal and hyperplastic breast, TSP1 and CD51 are expressed in the basement membrane and in the basal surface of myoepithelial cells, respectively. In lactating adenomas, both TSP1 and CD51 disappear from the myoepithelial-stromal junction of ducts. However, TSP1 becomes selectively expressed at the apices of secretory epithelial cells of lactating ducts together with CD36, suggesting that the distribution of TSP1 and the appearance of its receptors are dependent on the secretory activity of human mammary ducts. In neoplastic human breast, a strong immunostaining for TSP1 is observed in the basement membrane surrounding in situ carcinomas (preinvasive cancer), and excessive TSP1 deposits are also observed in desmoplasia of invasive ductal carcinomas. TSP1 mRNA is localized in myoepithelial cells surrounding in situ carcinomas and in fibroblasts present in desmoplastic areas. On the other hand, few invasive ductal carcinoma cells (10%) express TSP1, while CD51 is moderately expressed by some neoplastic clusters, and no immunoreactivity is observed for CD36. By contrast, TSP1 is codistributed with CD51 in most of the invasive lobular carcinoma cells (40 to 80%) and with CD36 in a subpopulation (30 to 40%) of these invasive tumor cells. As previously observed with lactating adenomas, it is likely that the coexpression of TSP1 and CD36 is related to the secretory activity of invasive lobular carcinoma cells. The different distribution of TSP1 in invasive ductal versus lobular carcinomas may well reflect biological differences between these two main types of breast carcinoma. In this regard, the coexpression of TSP1 and CD36 may, in part at least, account for the variably invasive behavior of lobular carcinoma cells.