Abstract 4389: Therapeutic opportunities of RANK pathway in breast cancer

Abstract

Abstract RANK pathway, key in bone remodeling and metastasis, is essential for mammary gland development. Using genetic mouse models we have previously shown that RANKL is the main mediator of the protumorigenic role of progesterone in the mouse mammary gland. RANK overexpression in non-transformed human mammary cell lines induces epithelial to mesenchymal transition and stemness, and promotes tumorigenesis and metastasis in breast cancer lines. RANK is expressed in a subset of basal and luminal human adenocarcinomas. Our goal is to determine a putative association of RANK and RANKL expression in breast adenocarcinomas with clinical parameters and to evaluate the functional role of RANK signaling using patient derived orthoxenografts of breast cancer. We have analyzed RANK and RANKL expression levels in an extensive collection of human breast adenocarcinomas collected from multiple centers, enriched in metastatic tumor samples. From the 318 patients with breast adenocarcinomas 138 developed metastasis. RANK expression is found on tumor cells but also on stromal cells, including tumor associated macrophages. RANKL is strongly expressed in some tumors, although the frequency is low. Analyses of RANK and RANKL mRNA and protein expression has been performed in multiple models of patient derived breast orthoxenografts. Several models with variable levels of RANK as well as RANKL expression have been identified and established in the laboratory. Functionality of the pathway was corroborated analyzing NF-kB activation upon in vitro and in vivo treatments with RANKL, in order to activate RANK signaling, or with RANK-Fc to inhibit it. We found that RANKL treatment induced NF-kB activation even in tumor cells with low levels of RANK expression. Citation Format: Hector Perez Montoyo, Jorge Gomez Miragaya, Eva M. Trinidad, Antonio Martinez-Aranda, Maria Teresa Soler Monso, Anna Petit, Angels Sierra, Eva Gonzalez Suarez. Therapeutic opportunities of RANK pathway in breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4389.