Our previous studies, which utilized 3D tumor spheroids in vitro cultured in the absence of myoepithelial cells or other cellular tumor microenvironment components, revealed a similar differential resistance of the outer, matrix-attached cells treated with PI3K and/or mTOR inhibitors.1 In the in vivo DCIS-like model presented here, BCL2 upregulation was clearly enriched specifically in the outer, niche-localized drug resistant tumor cell populations. The gene discussed is PIK3CA; the disease is ductal breast carcinoma in situ.