Despite significant progress in the treatment of breast cancer, the transition of pre-invasive ductal carcinoma in situ (DCIS) to more aggressive invasive ductal carcinoma (IDC) remains unknown. No prognostic biomarkers can reliably predict the risk of progression from DCIS to IDC. Similar genomic profiles of matched pre-invasive DCIS and IDC suggests that the progression is not driven by genetic aberrations in DCIS cells, but microenvironmental factors, such as hypoxia and metabolic stress prevalent in DCIS, may drive the transition.