Progestins Initiate a Luminal to Myoepithelial Switch in Estrogen-Dependent Human Breast Tumors without Altering Growth

Abstract

Although long-term clinical use of progestins is associated with an increased incidence of breast cancers, their role in established cancers is unclear. Estrogens are considered to be the main mitogens in the majority of breast cancers. Whether progesterone affects proliferation and/or differentiation is under debate. To assess the role of progesterone in established breast cancers, we used T47D human breast cancer cells that are estrogen receptor (ER) positive and either progesterone receptor (PR) negative or positive for PRA, PRB, or both. These cells were grown as strictly estrogen-dependent solid tumors in ovariectomized female nude mice. Progesterone or medroxyprogesterone acetate (MPA) alone did not support tumor growth, nor did progesterone or MPA given simultaneously with estrogen significantly alter estrogen-dependent tumor growth. However, treatment of mice bearing ER+PR+ but not ER+PRÀ tumors with either progesterone or MPA increased expression of the myoepithelial cytokeratins (CK) 5 and 6 in a subpopulation of tumor cells. These CK5+/CK6+ cells had decreased expression of luminal epithelial CK8, CK18, and CK19. We conclude that progestins exert differentiative effects on tumors characterized by transition of a cell subpopulation from luminal to myoepithelial. This may not be beneficial, however, because such a phenotype is associated with poor prognosis. (Cancer Res 2005; 65(21): 9779-88)

Rare steroid receptor-negative basal-like tumorigenic cells in luminal subtype human breast cancer xenografts

“…The growth of T47D human breast cancer cells into solid tumors in these mice has been described in ref. 19. For the current experiments, tumors were grown in the no.…”

“…4 mammary glands for 8 -10 weeks. Animals were supplemented with silastic implants containing estradiol only or estradiol plus the progestin MPA (19).…”

“…Immunohistochemistry on paraffin sections of tumors was described (19). For the current studies, samples were stained with a single-mouse mAb (CK5, CD44, CD24, PR) and visualized by using the Envision system (Dako) or dual stained by using the antibody combinations CK5/CD44, CK5/PR, and CD44/PR, where the second antibodies were rabbit mAbs.…”

“…of the basal receptor-negative subtype of breast cancers (19). These CK5 ϩ cells lack the basal epithelial marker CK14 and the myoepithelial marker smooth muscle actin and increase severalfold in number when progestins are given during tumor growth (19).…”

“…These CK5 ϩ cells lack the basal epithelial marker CK14 and the myoepithelial marker smooth muscle actin and increase severalfold in number when progestins are given during tumor growth (19). To characterize these cells, CK5 ϩ and CK5 Ϫ cells were isolated from tumor xenografts grown in mice treated with estradiol alone or with estradiol plus the progestin medroxyprogesterone acetate (6␣-methyl-17␣-hydroxyprogesterone acetate, MPA), using laser-capture microdissection of frozen tumor sections immunost ained for CK5 [supporting infor mation (SI) Text].…”