Abstract IA13: Wnt and Fgf signaling in mammary stem cells and breast cancer

Abstract

Abstract Some of the earliest evidence implicating both Wnt and FGF signaling in mammary tumorigenesis came from the observation of tumors in mouse mammary tumor virus (MMTV)- infected mice. Tumors arising from MMTV proviral insertion often exhibited preferential activation of Wnt and FGF pathway members. Interestingly, tumors with MMTV-induced expression of these FGF pathway ligands also showed MMTV-induced activation of Wnt pathway members, and functional cooperativity of MMTV-driven Wnt 1 and Fgf-3 transgenes in mammary tumorigenesis was observed. High throughput MMTV insertional mutagenesis studies have indicated that activation of Wnt and FGF pathway components is the most common occurrence in resulting tumors, providing definitive genetic proof for the cooperativity between these two pathways. Unraveling the complexity of these pathways in the context of development and tumorigenesis remains an evolving challenge. While the Wnt/ß-catenin cascade plays a central role in a range of biological processes, it has emerged as a key regulator of stem cell dynamics in multiple tissues, including the mammary gland. Significant evidence now implicates the Wnt/ß-catenin pathway in uncontrolled self-renewal of cancer stem cells and their associated radiation resistance during treatment. In the mammary gland, localized Wnt signaling most likely plays a critical role in regulating oriented cell division and cell fate. As with many signaling pathways, this is not an “on and off switch”, but is instead influenced by the level and duration of the signaling event. There are also Wnt-mediated ß-catenin-independent pathways, known as noncanonical Wnt cascades. For instance, noncanonical Wnt signaling through the receptor Ror2 helps to specify the extent and location of canonical Wnt/ß-catenin signaling. With regard to FGF signaling, FGFR1 and FGFR2, the two primary FGFRs expressed in mouse mammary epithelium, also are critical for mammary stem cell maintenance. Cooperation of the FGF and Wnt pathways in mammary tumorigenesis is based in part on the activation of protein translational pathways that result in, but are not limited to, increased expression of Wnt/β-catenin target genes at the level of protein translation. Lastly, Wnt and Fgf ligands can be regulated by systemic steroid hormones and act in a paracrine manner to influence mammary stem cells, providing another layer to the signaling hierarchy. Supported by grant NIH-CA16303. Citation Format: Jeffrey M. Rosen, Xue Bin, Kevin Roarty. Wnt and Fgf signaling in mammary stem cells and breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr IA13.