Abstract
Mammary gland branching morphogenesis and ductal homeostasis relies on mammary stem cell function for the maintenance of basal and luminal cell compartments. The mechanisms of transcriptional regulation of the basal cell compartment are currently unknown. We explored these mechanisms in the basal cell compartment and identified the Co-factor of LIM domains (CLIM/LDB/NLI) as a transcriptional regulator that maintains these cells. Clims act within the basal cell compartment to promote branching morphogenesis by maintaining the number and proliferative potential of basal mammary epithelial stem cells. Clim2, in a complex with LMO4, supports mammary stem cells by directly targeting the Fgfr2 promoter in basal cells to increase its expression. Strikingly, Clims also coordinate basal-specific transcriptional programs to preserve luminal cell identity. These basal-derived cues inhibit epidermis-like differentiation of the luminal cell compartment and enhance the expression of luminal cell-specific oncogenes ErbB2 and ErbB3. Consistently, basal-expressed Clims promote the initiation and progression of breast cancer in the MMTV-PyMT tumor model, and the Clim-regulated branching morphogenesis gene network is a prognostic indicator of poor breast cancer outcome in humans.
Highlights
Mouse mammary gland morphogenesis begins during midgestation with the development of two bilateral epithelial ridges along the ventral epidermis that form invasive, multipotent stem cell-enriched placodes migrating into the underlying mesenchyme, later branching to form a rudimentary ductal tree by birth
Because of the lethality of germline Clim2 deletion and the possible overlap in function between Clim1 and Clim2, we investigated the role of Co-factor of LIM domains (Clim) in the mammary gland using the Keratin 14 (K14) promoter to express a dominant-negative Clim (DN-Clim), consisting of the highly conserved LIM-interacting domain (LID) fused to a nuclear localization signal and Myc-tag [22], directing its expression to basal mammary epithelial cell (MEC)
While branching morphogenesis is typically completed by week 10, as denoted by the absence of terminal end buds (TEBs), small DN-Clim TEBs persist beyond 10 weeks of age (Figure 1H)
Summary
Mouse mammary gland morphogenesis begins during midgestation with the development of two bilateral epithelial ridges along the ventral epidermis that form invasive, multipotent stem cell-enriched placodes migrating into the underlying mesenchyme, later branching to form a rudimentary ductal tree by birth. Mammary stem cells (MaSCs) coordinate ductal morphogenesis and homeostasis of the luminal and basal cell compartments in the adult mammary gland. Two models have been proposed for the function of MaSCs in the mammary gland: either committed unipotent luminal and basal epithelial stem cells maintain their respective compartment [3], or bipotent MaSCs in the basal cell compartment give rise to both lineages [4]. CD49fHiCD29HiCD24+ basal epithelial cells maintain a small population of basal stem cells (BSCs) with the potential to regenerate a functional mammary gland [5,6], while luminal stem cells (LSCs), enriched in the CD49fLuCD29LuCD24+ luminal epithelial cell population, maintain unipotent potential to preserve the luminal cell population [3,4] and cannot regenerate the mammary gland. Transcription factors that control the maintenance of stem cells and lineage specification along the mammary epithelial cell (MEC) hierarchy are best characterized in the luminal cell compartment [7]. The current knowledge of transcriptional regulation of BSCs and their differentiation is limited
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