Beschreibung:
Abstract The Ron receptor tyrosine kinase is overexpressed in a high fraction of human breast cancers (BCs). Ron and its ligand, the Hepatocyte Growth Factor-Like protein (HGFL), play important roles during BC initiation, progression, and therapeutic resistance, with overexpression of this signaling cascade associated with increased BC metastasis and poor prognosis in humans. Reports demonstrate that a small subpopulation of cancer cells, called the breast cancer stem cells (BCSCs), are essential for the development and maintenance of BC, leading to tumor formation and recurrence. Despite the role of HGFL-Ron signaling as a key regulator of BC, nothing is known about this signaling pathway in BCSC populations. To investigate the function of HGFL-Ron signaling in BCSCs, the expression levels of Ron and HGFL were analyzed in BCSCs. mRNA analyses show increased levels of Ron and HGFL in BCSC-enriched Mammospheres (MSs) compared to parental BC epithelial cells. Next, the association between Ron signaling and the BCSC population was examined. Aldefluor assays of several Ron replete and depleted human and murine BC epithelial cell lines show that Ron overexpression increases the BCSC population. In vivo, flow cytometry analyses of breast tumors for BCSC markers show that Ron signaling is associated with increases in the BCSC population. MS formation assays using several Ron replete and depleted human and murine BC cell lines also demonstrate that cells expressing high levels of Ron have increased MS formation. Ex vivo studies of sorted BCSCs further support that Ron signaling enhances the MS formation ability of BCSCs. Interestingly, our data suggest that both genetic ablation and chemical inhibition of Ron signaling is sufficient to decrease BCSC MS formation ability. Mammosphere culture over several passages also suggest that Ron signaling BCSCs have higher self-renewal capabilities than Ron deficient BCSCs, highlighting the role of HGFL-Ron signaling in regulating BCSC function. Recent preliminary studies correlate Ron signaling in BCSCs with increased β-catenin and NF-κB pathways, suggesting these as the potential molecular mechanisms through which Ron signaling promotes BCSC function in BC. Overall, our data provide (i) the first evidence demonstrating both HGFL and Ron as critical factors regulating the BCSC population and (ii) that this regulation might occur in a β-catenin and NF-κB pathway dependent manner. These studies suggest both Ron and HGFL as potential therapeutic targets to eradicate BCSCs and improve the outcome of BC patients. Citation Format: Sasha J. Ruiz-Torres, Susan E. Waltz. HGFL-Ron signaling enhances breast cancer stem cell populations. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr B41.