High hopes for RANKL: will the mouse model live up to its promise?

A role for progesterone in breast carcinogenesis is increasingly recognized. Breast cancer risk increases with the number of menstrual cycles a women experiences [1] and proliferation occurs in the breast epithelium during the luteal phase, when serum progesterone levels are high [2]. Moreover, postmenopausal women on hormone replacement therapy have increased breast cancer risk when taking combined estrogens and progestins but not with estrogens only [3].Receptor activator of NF-κB ligand (RANKL) is a tumor necrosis factor (TNF) family member originally identified as a dendritic cell survival factor involved in the regulation of T-cell-dependent immune response and subsequently shown to control bone remodeling by inducing osteoclast differentiation [4]. Analysis of RANK- and RANKL-deficient mice pointed to a role for this pathway in the mammary gland during pregnancy [5] and in mammary carcinoma metastasis to the bone [6].RANKL expression in the mammary epithelium is controlled by progesterone [7,8]. Recent work identified RANKL as a key paracrine mediator of progesterone-induced mouse mammary epithelial cell proliferation [9,10] and implicated the cytokine in stem cell control [11,12]. Systemic inhibition of RANKL signaling by intravenous injection of recombinant osteoprotegerin, its decoy receptor, blocked progesterone-induced proliferation in the mammary epithelium, suggesting RANKL may be used as a therapeutic target in the mammary gland [9].Schramek and colleagues [13] and Gonzalez-Suarez and colleagues [14] now induced mammary carcinomas in mice using the progestin medroxyprogesterone acetate (MPA) and the mutagenic agent 7,12-dimethylbenz(a) anthracene (DMBA) and demonstrate that RANKL is a key factor in this process. Over-expression of RANK by means of a mouse mammary tumor virus (MMTV)-driven transgene accelerated hyperplasia and tumor formation [14] whereas pharmacological inhibition of RANKL [13,14] and genetic inactivation of RANK in the mammary epithel