Novel progesterone target genes identified by an improved differential display technique suggest that progestin-induced growth inhibition of breast cancer cells coincides with enhancement of differentiation

被引:117
作者
Kester, HA [1 ]
vanderLeede, BM [1 ]
vanderSaag, PT [1 ]
vanderBurg, B [1 ]
机构
[1] NETHERLANDS INST DEV BIOL,HUBRECHT LAB,NL-3584 CT UTRECHT,NETHERLANDS
关键词
D O I
10.1074/jbc.272.26.16637
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 alpha 1, 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 alpha 1, 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.
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页码:16637 / 16643
页数:7
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