Like birds flying south for the winter, cancer cells can migrate from the site of the primary tumour and disseminate around the body. But what signals turn a non-invasive cancer cell into a metastatic cell? Using a unique in vitro system that models the early stages of breast cancer, Joan Brugge and colleagues show that ERBB2 and transforming growth factor-β (TGF-β) work together to cause invasion and migration of breast cancer cells.

Under certain culture conditions, MCF10A cells that are engineered to express activated ERBB2 (10A.B2 cells) produce structures that share properties with ductal carcinoma in situ (DCIS), an early-stage, non-invasive breast cancer. So, 10A.B2 cells were infected with retroviral vectors expressing breast-cancer-associated cDNAs to identify factors that could promote metastasis. Only TGF-β1 and TGF-β3 increased migration of the activated 10A.B2 cells, indicating that ERBB2 and TGF-β might cooperate to induce migration. Soluble TGF-β had a similar effect, although to a lesser extent, indicating that autocrine TGF-β stimulation is particularly important. Furthermore, this induction of migration seems to be dependent on ERBB2, as TGF-β1 and TGF-β3 had no effect on MCF10A cells expressing the activated epidermal growth factor receptor ERBB1.

Various assays confirmed that TGF-β1 and TGF-β3 expression induced migration and invasion of activated 10A.B2 cells. As the extracellular signal-regulated kinase ERK is implicated in migration and is activated by ERBB2 and TGF-β, the authors investigated ERK activity in the TGF-β-expressing 10A.B2 cells. Phosphorylation of both ERK and the ERK kinase MEK was increased in these cells compared with controls, indicating that TGF-β and ERBB2 increase ERK activation. This was investigated further by expressing TGF-β and activated MEK in the absence of activated ERBB2; migration and invasion were substantially increased, compared with controls expressing activated MEK alone. So, MEK activation is insufficient to induce migration and invasion, but it can substitute for ERBB2 in the presence of TGF-β. MEK inhibitors reduced migration of TGF-β-expressing 10A.B2 cells by 85% and invasion by 65%, confirming that ERK activation is required for the synergism between TGF-β and ERBB2.

How might ERBB2 and TGF-β induce this migration? Cultured medium from activated TGF-β-expressing 10A.B2 cells induced migration of MCF10A cells, but mixing cultured medium from cells expressing either TGF-β or activated ERBB2 alone did not enhance migration, indicating that TGF-β and ERBB2 must cooperate to produce soluble migratory factors. ERBB1-specific antibodies reduced the stimulating activity of the cultured medium by 50–60%, indicating that other pathways contribute to migratory activity.

As about 80% of DCIS lesions express ERBB2, this work indicates that TGF-β expression could represent one step in the process that turns a non-invasive tumour into metastatic breast cancer.