Few studies have documented the role of β3 integrin in the spontaneous spread of breast tumours to bone due to the lack of clinically relevant animal models. Published evidence for its role in regulating tumour growth and angiogenesis is controversial. Moreover, many questions remain regarding the relative contribution of tumour versus stromal β3 integrin to metastasis to bone. To address this, we measured the impact of stable downregulation of tumour β3 expression on spontaneous and experimental metastasis using aggressive bone metastatic lines isolated in our laboratory (4T1.2 and 4T1BM2). The role of stomal β3 integrin in metastasis was evaluated in integrin β3 wild-type and null mice.
Interestingly, suppression of tumour β3 dramatically reduced spontaneous but not experimental (intracardiac tumour injection) metastasis to spine and femurs indicating that tumour β3 is required early during metastasis. In addition, suppression of tumour β3 or treatment of the cells with a β3 inhibitor (DisBa-01) unexpectedly resulted in a visible increase in the incidence of experimental metastasis to soft tissues. Thus, suppression or pharmacological inhibition of tumour β3 integrin may alter the metastatic pattern of disseminated breast tumour cells and lead to enhanced soft tissue metastasis.
Contrary to previous studies in melanoma, the lack of stromal β3 expression did not impact significantly on 4T1.2 or 4T1BM2 spontaneous metastasis to bone ruling out a critical role for stromal β3 in this process. Moreover, we found that the loss of stromal β3 expression did not impact on 4T1BM2 primary tumour growth or vascularisation when implanted orthotopically. In contrast, subcutaneous tumour growth and angiogenesis was enhanced in β3-null mice indicating that regulation of tumour growth and vascularisation by β3-expressing stromal cells is site-specific. Taken together, these observations have important clinical implications for the design of anti-metastatic therapies targeting β3 integrin in advanced breast tumours.