The progression of ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) for breast cancer patients results in a significantly poorer prognosis and is the precursor to metastatic disease. To undergo this invasive switch, the cancer cells must breach either the vascular or ductal basement membrane as they begin to infiltrate the surrounding stroma. During the development of a triple-culture platform, whereby endothelial cells were seeded below a fibroblast-contracted collagen matrix with invading cancer cells, we observed a clear reduction in cancer cell invasion into the matrix in the presence of the endothelial cells. Data mining of endothelium secretome components, followed by invasion screening, identified IGFBP2 as the endothelial-secreted paracrine anti-invasive factor. In order to assess the disease-specific relevance of IGFBP2, we stained samples from normal reduction mammoplasty patients and found that adipocytes in the healthy tissue had a clear IGFBP2 signal. Furthermore, mature adipocytes differentiated from patient-derived pre-adipocytes were found to secrete IGFBP2, which significantly inhibited breast cancer invasion in inverted invasion and organotypic matrix assays in vitro. Flow cytometry showed no cell surface binding of IGFBP2, and the effect of IGFBP2 on the extracellular matrix did not appear significant. Hence, to identify the mechanism we turned to the canonical role of IGFBP2, which is to bind and regulate the levels of IGFI/II available for tissues. Proteomics experiments validated IGFII as the primary factor bound to IGFBP2 in the cancer cell conditioned media. In line with IGFBP2 binding IGFII, depletion of IGFII in invading cancer cells using siRNAs or an IGFII neutralising-antibody ablated breast cancer invasion, highlighting the importance of IGFII autocrine signalling for breast cancer invasive progression. Given the abundance of adipocytes in the normal breast, this work exposes the important role they play in suppressing cancer progression and may help to expound upon the link between increased mammary density and poorer prognosis.