Sox10 Regulates Stem/Progenitor and Mesenchymal Cell States in Mammary Epithelial Cells

Abstract

Summary To discover mechanisms that mediate plasticity in mammary cells, we characterized signaling networks that are present in the mammary stem cells responsible for fetal and adult mammary development. These analyses identified a signaling axis between FGF signaling and the transcription factor Sox10. Here we show that Sox10 is specifically expressed in mammary cells exhibiting the highest levels of stem/progenitor activity. This includes fetal and adult mammary cells in vivo and mammary organoids in vitro. Sox10 is functionally relevant, as its deletion reduces stem/progenitor competence, while its overexpression increases stem/progenitor activity. Intriguingly, we also show that Sox10 overexpression causes mammary cells to undergo a mesenchymal transition. Consistent with these findings, Sox10 is preferentially expressed in stem- and mesenchymal-like breast cancers. These results demonstrate a signaling mechanism through which stem and mesenchymal states are acquired in mammary cells, and suggest therapeutic avenues in breast cancers for which targeted therapies are currently unavailable.

Expression Profiling of Clinical Specimens Supports the Existence of Neural Progenitor-Like Stem Cells in Basal Breast Cancers

“…The results of our analysis are consistent with the existence in BBC of SOX10+/CD133+ cells with NSC properties and major role proposed for SOX10 in breast stem cell maintenance 17 . Tracking CSC in BBC using novel markers that we identified offers new research tools and approaches to improve BBD diagnostics, prognostication, and treatment.…”

“…Interestingly, we and others previously demonstrated that SOX10 expression is also diagnostic for basal-like breast carcinoma (BBC), a breast cancer subtype distinguished with myoepithelial-like gene expression profile and myoepithelial differentiation akin to ACC 8, 13, 14, 17 . BBC as a triple-negative breast cancer (TNBC) subtype was described 15 years ago based on a characteristic gene expression signature found in ~15% of breast cancer specimens 20–22 .…”

“…A remarkable example of such a marker is SOX10 (SRY-related HMG box-containing factor 10), which plays pivotal roles in gliogenesis, melanogenesis, differentiation of myoepithelial cells and other lineages that originate from neural crest, and maintenance of adult neural stem cells (NSC) that reside in the subventricular CNS zone 7–12 8, 13–15 . Recent studies that characterized SOX10 as a melanoma driver 16 , and a key breast stem cell regulator 17 raised the important question about SOX10 relevance to stem cell maintenance in a certain group of cancers.…”

WNT-Mediated Regulation of FOXO1 Constitutes a Critical Axis Maintaining Pubertal Mammary Stem Cell Homeostasis

“…Studies have since attempted to refine the identity of MaSCs. Accordingly, these studies leverage previously identified stem cell properties, such as expression of transcriptional regulators of ‘stemness’ (Chakrabarti et al, 2014; Junankar et al, 2015), stem cell-maintaining WNT pathway activity (de Visser et al, 2012; Plaks et al, 2013; van Amerongen et al, 2012; Wang et al, 2015), mesenchymal cell properties (Dravis et al, 2015; Guo et al, 2012), or markers of quiescence (Cai et al, 2016; dos Santos et al, 2013; Fu et al, 2017). However, no single, robust, pan-MaSC marker has emerged, suggestive of heterogeneity within the MaSC pool.…”

Sox10+ adult stem cells contribute to biomaterial encapsulation and microvascularization

“…In recent years, Sox10 + stem cells have been reported to exist in multiple adult tissues, including inferior turbinate23, periodontal ligament24, hair follicle2526, mammary epithelium27, and bone marrow28. Sox10 could also promote tumor formation29.…”