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The receptor activator of nuclear factor-kB (NF-kB) (RANK)/receptor activator of NF-kB ligand (RANKL) axis emerges as a key regulator of breast cancer initiation, progression and metastasis. RANK receptor is a tumor necrosis superfamily member, which upon ligand binding transduces a variety of survival, proliferation, differentiation and migration signals. The majority of these intracellular cues merge through the NF-kB transcription machinery.    Methods   TNFRSF11A  (RANK) variants were identified and cloned in mammalian expression vectors. Their expression was analyzed using real time PCR on RNA from normal tissue, cell lines and breast cancer specimens. Western blot analysis and immunofluoresence stainings were used to study expression and localization of protein isoforms in a panel of breast cancer cell lines and in transfected 293T cells. Luciferase assays were employed to assess the contribution of each isoform alone or in combinations on NF-kB activation. Isoform effect on cell survival after doxorubicin treatment was analyzed through MTT assay. Wound healing and transwell assays were employed to evaluate the effect of TNFRSF11A isoforms on migration of MDA-MB-231 and 293T cells.    Results  We report the identification of three novel  TNFRSF11A  (RANK) variants, named  TNFRSF11A_Δ9 ,  TNFRSF11A_Δ8,9  and  TNFRSF11A_Δ7,8,9  which result from the alternative splicing of exons 7 to 9. Interestingly, variant  TNFRSF11A_Δ7,8,9  was found to be upregulated in breast cancer cells lines and its expression inversely correlated with tumor grade and proliferation index.  TNFRSF11A_Δ7,8,9  encodes a 40-45 kDa protein, we named RANK-c, which lacks the transmembrane domain and most of the intracellular part of the wild type receptor. Furthermore, we showed that RANK-c could act as a dominant negative regulator of RANK-dependent NF-kB activation, affecting cell survival after apoptosis induction. In addition, RANK-c suppresses cell migration and represses the tumorigenic properties of invasive breast carcinoma cells.    Conclusions  In this study, we provide evidence of a complex regulatory network of RANK receptor splice variants with a role in breast cancer. We identify that the RANK-c isoform is expressed in breast cancer samples and its expression reversely correlates with histological grade. Finally, isoform RANK-c seems to have the capacity to regulate signaling through wild type RANK and moreover to inhibit cell motility and migration of breast cancer cells.

breast cancer research

Identification of novel human receptor activator of nuclear factor-kB isoforms generated through alternative splicing: implications in breast cancer cell survival and migration