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

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 identifi ed 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 diff erentiation [4]. Analysis of RANKand RANKL-defi cient 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 identifi ed RANKL as a key paracrine mediator of progesteroneinduced 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 recep tor, blocked progesterone-induced prolifera tion 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 forma tion [14] whereas pharmacological inhibition of RANKL [13,14] and genetic inactivation of RANK in the mammary epithelium [14] decreased incidence and delayed onset of tumorigenesis in this system. To investigate whether RANKL is similarly important in the pathogenesis of other tumor types that arise independently of exogenous hormones, Gonzalez-Suarez and colleagues used the MMTV-neu transgenic mouse model. Interestingly, in ErbB2-driven carcinogenesis, pharmacological inhibition of RANKL also reduces tumor growth and lung metastasis, suggesting that the RANK signaling pathway may be of functional relevance in a wider tumor spectrum. Th is is of great clinical interest given the heterogeneity of human breast cancer. Schramek and colleagues observe that RANK deletion does not alter the incidence of mammary cancer in MMTV-neuT transgenic mice. It is conceivable that the apparent discrepancy results from Keratin5-cre RANK deleted cells being outgrown by MMTV-neuT cells that have kept the wild-type RANK allele. Abstract