Niche-localized tumor cells are protected from HER2-targeted therapy via upregulation of an anti-apoptotic program in vivo

Preservation of niche-localized tumor cells post-lapatinib treatment. Representative H&E images of vehicle-treated (a–e) and 5-day or 10-day lapatinib-treated (f–j) SUM225 DCIS-like tumors. Note f, g, i were 10-day whereas h was 5-day lapatinib-treated. The lapatinib-treated tumor images represent the spectrum of responses observed, with the least significant reductions in the viable tumor cell content shown in (f). Note cell crypts (vacuole-like spaces throughout the cell layer) associated with the areas of cell death. More significant reduction in the viable tumor cell content is shown in (g, h), with maintenance of only the outermost layer of tumor cells adjacent to myoepithelial cells and BM in (h). HER2 immunostains confirm HER2 status among the residual tumor cell population (j). H&E (d, i) and serial section HER2 IHC (e, j) are presented. Note d, e, i, j represent longitudinal sections, whereas all other panels represent transverse sections, through the intraductal tumors. Comparison of vehicle (k–m) and 21-day lapatinib-treated (n–p) SUM225 tumors. Representative H&E (k, n) and serial section HER2 IHC (l, m) and (o, p) are presented. Arrowheads in l, o highlight the regions in m, p. Note preservation of the niche-localized HER2+ tumor cells post-long term lapatinib treatment (p). Scale bar, ~200？μ