Absence of estrogen receptor (ER) and progesterone receptor (PR) is the hallmark of most hormone-independent breast cancers. Previous studies demonstrated that reactivation of PR expression in hormone-independent MDA-MB-231 breast cancer cells enabled progesterone to suppress cell growth both in vitro and in vivo. We determined the whole genomic effect of progesterone in PR-transfected MDA-MB-231 cells. We identified 151 progesterone-regulated genes with expression changes > 3-fold after 24 hr treatment. Most are novel progesterone target genes. Real-time RT-PCR analysis of 55 genes showed a 100% confirmation rate. Twenty-six genes were regulated at both 3 and 24 hr. Studies using translation inhibitor suggest that most of the 26 genes are primary progesterone target genes. Progesterone consistently suppressed the expression of genes required for cell proliferation and metastasis and increased the expression of many tumor-suppressor genes. Progesterone also consistently decreased the expression of DNA repair and chromosome maintenance genes, which may be part of the mechanism leading to cell cycle arrest. These data suggest potential usefulness of progestin in combating ER-negative but PR-positive breast cancer and indicate that progesterone can exert a strong anticancer effect in hormone-independent breast cancer following PR reactivation. The identification of many novel progesterone target genes open up new avenues for in-depth elucidation of progesterone-mediated molecular networks.
Copyright 2005 Wiley-Liss, Inc.