Progesterone is an important regulator of normal and malignant breast epithelial cells. In addition to stimulating development of normal mammary epithelium, it can be used to treat
hormone-dependent
breast tumors. However, the mechanism of growth inhibition by
progestins is poorly understood, and only a limited number of
progesterone target genes are known so far. We therefore decided to clone such target genes by means of differential display polymerase chain reaction. In this paper, we describe an improved differential display strategy that eliminates false positives, along with the identification of nine positive (
TSC-22, CD-9, Na+/K+-
ATPase alpha1,
desmoplakin, CD-59, FKBP51, and three unknown genes) and one negative
progesterone target genes (
annexin-VI) from the mammary
carcinoma cell line T47D, which is growth-inhibited by
progestins. None of these genes have been reported before to be
progesterone targets. Regulation of
desmoplakin, CD-9, CD-59, Na+/K+-
ATPase alpha1, and
annexin-VI by the
progestin suggests that
progesterone induces T47D cells to differentiate. Three of these genes were repressed by
estradiol and up-regulated by the
progestin.
Estradiol treatment of T47D cells also leads to formation of lamellipodia and delocalization of two cell adhesion
proteins,
E-cadherin and
alpha-catenin. All these effects were reversed by the
progestin. These data suggest that
estradiol dedifferentiates T47D cells, while
progestins have the opposite effect. This may be linked to the capacity of
progestins to inhibit
tumor growth.