Abstract

Risk of recurrence and progression of ductal carcinoma in situ (DCIS) to invasive cancer remains uncertain, emphasizing the need for developing predictive biomarkers of aggressive DCIS. Human cell lines and mouse models of disease progression were analyzed for candidate risk predictive biomarkers identified and validated in two independent DCIS cohorts. RNA profiling of normal mammary and DCIS tissues (n?=?48) revealed that elevated SOX11 expression correlates with MKI67, EZH2, and DCIS recurrence score. The 21T human cell line model of DCIS progression to invasive cancer and two mouse models developing mammary intraepithelial neoplasia confirmed the findings. AKT activation correlated with chromatin accessibility and EZH2 enrichment upregulating SOX11 expression. AKT and HER2 inhibitors decreased SOX11 expression along with diminished mammosphere formation. SOX11 was upregulated in HER2+ and basal-like subtypes (P?<?0.001). Longitudinal DCIS cohort (n?=?194) revealed shorter recurrence-free survival in SOX11+ than SOX11? patients (P?=?0.0056 in all DCIS; P?<?0.0001 in HER2+ subtype) associated with increased risk of ipsilateral breast event/IBE (HR?=?1.9, 95%CI?=?1.2–2.9; P?=?0.003). Epigenetic activation of SOX11 drives recurrence of DCIS and progression to invasive cancer, suggesting SOX11 as a predictive biomarker of IBE.