Abstract 1960: Sox10 expression labels mammary stem cell activity in fetal, adult, cultured, and male mammary tissues and is attenuated by FGF signaling inhibition

Abstract

Abstract Molecular pathways that guide cell proliferation and programming events during embryonic development may be aberrantly re-activated in the cancer state to drive tumor progression. We have demonstrated the applicability of this tenet to studies of breast cancer. We have isolated fetal mammary stem cells (fMaSCs) from embryonic mammary rudiments, and verified that particular subtypes of breast cancers, including Basal-like triple-negative breast cancers, show strong correlation with expression signatures found in fMaSCs. This suggests that elucidation of the biology behind fMaSC function will yield insight into better treatment of these aggressive breast cancers. Through transcriptome analysis of fMaSCs, the transcription factor Sox10 was identified as a potential mediator of MaSC-activity. By analyzing a Sox10-Venus reporter line, we have discovered that Sox10 labels fMaSCs in the embryo, and improves recovery of fMaSC-enriched populations threefold over previous markers. Intriguingly, Sox10 also permits the first identification and recovery of male fMaSCs, which also demonstrate stem cell behaviors in vitro and in vivo. In the adult mammary gland, Sox10 only labels a subset of mammary cells, yet these cells possess all in vitro colony-forming potential compared to Sox10-negative cells. Of interest, both Sox10+ and Sox10-negative adult mammary cells demonstrate in vivo stem cell behaviors, suggesting the presence of unique multipotent MaSC populations. We find that Sox10 is also highly enriched in Basal-like breast cancers. Per previous studies with Sox9 and Sox10 in pancreatic and skin cancer models, Sox10 may play critical roles in the progression of Basal-like breast cancer. Molecular pathways that regulate Sox10 expression may therefore be useful therapeutic targets for treating Basal-like breast cancers. We find that perturbation of FGF signaling significantly attenuates Sox10 expression in organoids grown in vitro that are derived from either fMaSCs or luminal progenitors. As Sox10+ cells in mammary organoids specifically possess and label retained MaSC properties that are not seen in Sox10-negative cells, this may indicate a mechanism to attenuate MaSC specification or function in mammary tissue. Our discoveries with Sox10 thus represent a molecular focal point around which to build signaling and transcriptional networks underlying fMaSC state and function. To capitalize on this, we have performed RNA-sequencing on fetal and adult mammary populations using Sox10 as a marker. These analyses combine significantly purer cell fractions with a sequencing tool capable of most accurately profiling transcription events. This is expected to provide highest quality transcriptome data describing signaling events in these mammary tissues, which will identify potential therapeutic targets for different subtypes of breast cancer. Citation Format: Christopher Dravis, Geoff Wahl. Sox10 expression labels mammary stem cell activity in fetal, adult, cultured, and male mammary tissues and is attenuated by FGF signaling inhibition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1960. doi:10.1158/1538-7445.AM2014-1960