It is possible that this population is involved in progression of DCIS lesions to IDC and serves as a malignant precursor cell[22]. We investigated stem cell signaling in both DCIS and triple

negative invasive breast cancer models, focusing on stem cell regulators Bosentan hydrate 147536-97-8 SOX2 and SOX9. CSC signaling There are a number of pathways associated with deregulated self-renewal in cancer stem cells, including the Notch, Sonic hedgehog, Wnt, and Pluripotency factor pathways[18]. Dysregulation in these signaling pathways is common in breast cancer. The Notch pathway is involved in breast development, and dysregulation is an early event in DCIS. Notch is up regulated in breast cancer stem cells[23], and may be involved in DCIS stem cell mediated progression to IDC. The Wnt pathway is involved in regulation of stem cell proliferation. Deregulation of Wnt signaling and proliferation predisposes to cancer[24]. Overexpression

of Wnt is correlated with increased mammary tumor formation[25], an event mediated by cancer stem cells. Sonic hedgehog is also involved in regulating self-renewal of mammary stem cells as well as inhibiting differentiation, potentially through the Notch signaling pathway[26]. Hijacking of embryonic pluripotency factors (OCT4, SOX2, KLF4) has also been reported in cancer stem cells. Sry-related HMG box 2 (SOX2) has been reported to be an oncogene in early stage breast cancers[27]. Furthermore, we have identified a critical

role for the related HMG-box protein SOX9 in DCIS stem cells[28]. SOX2 and SOX9 SOX9 transcription factor is an important stem cell regulator and works cooperatively with Slug to promote tumorigenesis and cancer initiation. Slug is an epithelial-mesenchymal transition transcription factor, upregulated in mammary stem cell populations. When coexpressed with SOX9, differentiated mammary epithelial cells are converted into mammary stem cells[29]. SOX9 is overexpressed in a number of breast malignancies, and is necessary for mammosphere formation of basal DCIS cell lines. SOX9 expression increases with DCIS grade[28]. In basal like, IDC cell lines, expression of both Slug and SOX9 is necessary for tumor initiation; SOX9 is also necessary for maintaining tumorgenicity[29]. This may demonstrate a relationship between risk of progression from DCIS to IDC and an increase in cancer stem Carfilzomib cell population. SOX2, OCT4 and NANOG form a complex that binds promoters of numerous differentiation factors. Dysregulation of any member of this complex leads to aberrant self-renewal, a primary characteristic of cancer stem cells[27]. Overexpression of SOX2 is a common mechanism of aberrant self-renewal signaling, and is required for tumor-initiation. Stable knockdown of SOX2 in MCF-7 breast cancer cells results in a significant decrease in the CD44 high/CD24 low stem cell population.