Molecular Insights on the Transition of Non-invasive DCIS to Invasive Ductal Carcinoma

More than 90% of breast cancer-related deaths are caused by metastasis not primary tumor. To effectively reduce cancer mortality, it is extremely important to predict the risk of, and to intervene in, the critical transition from

More than 90% of breast cancer-related deaths are caused by metastasis not primary tumor. To effectively reduce cancer mortality, it is extremely important to predict the risk of, and to intervene in, the critical transition from non-invasive ductal carcinoma in situ （DCIS） to life-threatening invasive ductal carcinoma （IDC）. We found that 14-3-3 overexpression is a ＂second hit＂ or ＂risk factor＂ facilitating a subset of ErbB2-overexpressing DCIS transition into IDC. Mechanistically, 14-3-3 ζ overexpression activated TGFβ/ Smads pathway, increased Smad-interacting protein 1 （SIP-1） expression that induced epithelial-mesenchymal transition. Importantly, patients with DCIS lesions that express both high 14-3-3 ζ and TGFβRI showed at leasttwo EMT marker alterations （reduced epithelial marker E-cadherin, and expressed mesenchymal marker vimentin and/or N-cadherin） and these DCIS were diagnosed as high-grade DCIS （grade 3） with a higher risk of developing invasive recurrence.