c-Myb regulates matrix metalloproteinases 1/9, and cathepsin D: implications for matrix-dependent breast cancer cell invasion and metastasis

Ectopically expressed c-Myb enhanced migration and ability of human MDA-MB-231 and mouse 4T1 mammary cancer cells to invade Matrigel but not the collagen I matrix in vitro. c-Myb strongly increased the expression/activity of cathepsin D and matrix metalloproteinase (MMP) 9 and significantly downregulated MMP1. The gene coding for cathepsin D was suggested as the c-Myb-responsive gene and downstream effector of the migration-promoting function of c-Myb. Finally, we demonstrated that c-Myb delayed the growth of mammary tumors in BALB/c mice and affected the metastatic potential of breast cancer cells in an organ-specific manner.This study identified c-Myb as a matrix-dependent regulator of invasive behavior of breast cancer cells.Metastatic disease is the main cause of death in cancer patients. The interaction of tumor cells with local stroma plays a critical role in metastatic dissemination and determines metastasis organotropism. Identification of the genes providing cancer cells with the abilities to disseminate to specific organs is essential for targeting metastatic cells to improve patient survival.The c-Myb protein is a transcription factor that plays a key role in regulating the proliferation/differentiation of progenitor cells in bone marrow, colonic crypts, and neurogenic niches [1]. c-myb was originally identified as a cellular homolog of v-myb, the transforming retroviral oncogene linked to avian leukemia [2]. Since then, c-myb has been characterized as an oncogene in several human tumor types [3-7], including breast cancer [8-10]. The role of c-Myb in stimulating cell proliferation, suppressing differentiation, and apoptosis is well established [1,11]. However, only a few reports concerning the role of c-Myb in controlling tumor invasion have been reported. First, genes coding for some of the proinvasive factors, such as CXCL12 and CXCR4, were identified as c-Myb targets [12-14]. Second, c-Myb is involved in the regulation of epithelial-to-mesenchymal tra