PMC

Proposed differentiation pathway of ER⁺, PR⁺ breast cancers from ER⁻, PR⁻ stem cells, and the reversal induced by progestins. Data in support of this pathway are reported in Refs. , , and . All cells are CD44⁺, CD24^−/low (not shown). Tumors are also ER⁺, but PR, the targets of progestins, are mainly shown for simplicity. Without stimulating proliferation, both progesterone and MPA reactivate CK5 in ER⁺, PR⁺ cells within 24 h especially in young, germinal tumors. Restoration of steroid receptors to CK5⁺ stem-like cells does not require hormones. Mitogenic effects of estrogens occur in later stages of these pathways after cells have acquired ER and PR.

MPA reactivates stem-like properties in human breast cancer cells. Cells isolated from human ER⁺, PR⁺, xenografted, T47D cell-derived solid tumors were FACS sorted for CD44⁺ cells, plated into minimal medium in eight-well plates, and allowed to form colonies for 3–14 d. Cells were either vehicle treated (control) or treated with 10 nm of the progestin MPA for 24 h before fixation and immunostaining for CK5 (green) and PR (red) and counterstained with DAPI (blue). Because the cells express PR constitutively, no estrogen was required. Two young colonies (3 d, 10–15 cells), one control and one MPA-treated, are shown. Cells are either CK5⁺ (stem-like) or ER⁺, PR⁺ (more differentiated) but not both (ER are not shown). Arrow points to a rare PR⁺, CK5⁺, transient intermediate cell (see Fig. 2), usually found only in progestin-treated colonies. Scale bars, 10 μm. [Reproduced with permission from K. B. Horwitz et al.: Proc Natl Acad Sci USA 105:5774 (). ©The National Academy of Sciences.]