The extracellular matrix composition and responsiveness to breast carcinoma therapy

It is established that stroma surrounding breast carcinoma can be altered in comparison with its normal counterpart, and histological observations recognize lesions with loose stroma rich in hyaluronic acid (HA) and recognize lesions with dense stroma rich in fibulin-1, collagens, laminins, fibronectin and fibrillins. Previous studies have shown that adhesion of tumor cells to different extracellular matrix (ECM) components interferes with drug responses. Thus, to address the functional and biological behavior of the breast cancer-related ECM proteins in response to cytotoxic treatments, the breast carcinoma cell line MDAMB361 was injected into athymic mice in the presence of a matrix containing high levels of fibulin-1, laminin-1 and collagens. The grown tumors displayed significantly (P = 0.01) reduced sensitivity to DXR compared with the same cells injected without the matrix, strongly indicating that the ECM milieu of tumor impacts the responsiveness of tumor cells to drugs. The analysis of changes in the ECM components in response to DXR treatment revealed that the human breast carcinoma cell lines SKBR-3, MCF-7, MDAMB157 and MDAMB361 upmodulated fibulin-1 transcript [1] and protein levels, particularly in a form exhibiting a molecular weight (about 50 kDa) lower than expected (about 74 kDa), thus suggesting that tumor cells may actively reorganize their matrix environment. In parallel with the increase of fibulin-1 the same stress conditions determined decreased expression of hyaluronan synthetases, the enzymes involved in the synthesis of HA. These preliminary findings provide support for a role of ECM in response to drugs and suggest that reorganization of the ECM following chemotherapy is the basis of drug-induced resistance.