Fig. 9

Primary mammosphere formation in unmodified HER2+ BT474 breast cancer cells. a Primary mammospheres in HER2+ BT474 cells expressing endogenous estrogen receptor (ER) and progesterone receptor isoforms (PR-A and PR-B) plotted as a percentage of mammosphere forming efficiency (MFE; see “Methods”). Cells were treated with vehicle (EtOH) control or R5020 (10 nM) without or with increasing concentrations of the type II antiprogestin onapristone (0, 100, or 1000 nM). Data is represented as the average ± SD of three readings. *p < 0.05, **p < 0.01, ***p < 0.001 compared to vehicle control. Secondary mammospheres failed to form in onapristone-containing media (not shown). b, c Model depicting PR action in normal breast (b) vs. during neoplastic luminal tumor progression (c). Phosphorylation of PR Ser294 and p-PR target gene expression (HER2, RUNX2, AR, AHR, PAX2) in the cancer stem cell (CSC) or neighboring tumor cell compartments may occur during early luminal tumor progression of ER+/PR+ (luminal A type) breast cancers that progress toward ER+/PR-low (and HER2+) (luminal B type) tumors that are CSC-rich and thus more likely to become endocrine-resistant. Early addition of anti-progestins to anti-estrogen/ER-based therapies may prevent or delay the onset of endocrine therapy-resistant luminal breast cancer recurrence