Mammary stem cells and cancer: roles of Wnt signaling in plain view

Many, Alexander M.; Brown, Anthony M.

doi:10.1186/bcr2631

Cited by 11 publications

(4 citation statements)

References 14 publications

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“…As expected, the decrease in the Wnt/Notch signaling ratio is associated with a concomitant strong prodifferentiation and antiproliferation phenotype in basal stem/progenitor cells. Because a decrease in Wnt signaling is known to have an anticarcinogenic effect [24,25], the findings support the hypothesis that a reduction in the Wnt/Notch signaling ratio in basal mammary stem/progenitor cells plays a role in the mitigating effect of early pregnancy on breast tumorigenesis.…”

Section: Introductionsupporting

confidence: 66%

Parity induces differentiation and reduces Wnt/Notch signaling ratio and proliferation potential of basal stem/progenitor cells isolated from mouse mammary epithelium

et al. 2013

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IntroductionEarly pregnancy has a strong protective effect against breast cancer in humans and rodents, but the underlying mechanism is unknown. Because breast cancers are thought to arise from specific cell subpopulations of mammary epithelia, we studied the effect of parity on the transcriptome and the differentiation/proliferation potential of specific luminal and basal mammary cells in mice.MethodsMammary epithelial cell subpopulations (luminal Sca1-, luminal Sca1+, basal stem/progenitor, and basal myoepithelial cells) were isolated by flow cytometry from parous and age-matched virgin mice and examined by using a combination of unbiased genomics, bioinformatics, in vitro colony formation, and in vivo limiting dilution transplantation assays. Specific findings were further investigated with immunohistochemistry in entire glands of parous and age-matched virgin mice.ResultsTranscriptome analysis revealed an upregulation of differentiation genes and a marked decrease in the Wnt/Notch signaling ratio in basal stem/progenitor cells of parous mice. Separate bioinformatics analyses showed reduced activity for the canonical Wnt transcription factor LEF1/TCF7 and increased activity for the Wnt repressor TCF3. This finding was specific for basal stem/progenitor cells and was associated with downregulation of potentially carcinogenic pathways and a reduction in the proliferation potential of this cell subpopulation in vitro and in vivo. As a possible mechanism for decreased Wnt signaling in basal stem/progenitor cells, we found a more than threefold reduction in the expression of the secreted Wnt ligand Wnt4 in total mammary cells from parous mice, which corresponded to a similar decrease in the proportion of Wnt4-secreting and estrogen/progesterone receptor-positive cells. Because recombinant Wnt4 rescued the proliferation defect of basal stem/progenitor cells in vitro, reduced Wnt4 secretion appears to be causally related to parity-induced alterations of basal stem/progenitor cell properties in mice.ConclusionsBy revealing that parity induces differentiation and downregulates the Wnt/Notch signaling ratio and the in vitro and in vivo proliferation potential of basal stem/progenitor cells in mice, our study sheds light on the long-term consequences of an early pregnancy. Furthermore, it opens the door to future studies assessing whether inhibitors of the Wnt pathway may be used to mimic the parity-induced protective effect against breast cancer.

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Section: Introductionsupporting

confidence: 66%

Parity induces differentiation and reduces Wnt/Notch signaling ratio and proliferation potential of basal stem/progenitor cells isolated from mouse mammary epithelium

et al. 2013

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“…We propose a central mechanism that revolves around DKK1 and Kremen, in which canonical Wnt signaling is independently regulated in cancer cells and osteoblasts in bone metastasis. In breast cancer, Wnt signaling is clearly required for breast cancer cell proliferation and migration [50] , [51] . In breast cancer bone metastasis, TGF-β released from the bone matrix during osteolysis is a critical event that supports breast cancer growth in bone [52] .…”

Section: Discussionmentioning

confidence: 99%

DKK1 and Kremen Expression Predicts the Osteoblastic Response to Bone Metastasis

Clines

2018

Translational Oncology

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Bone metastasis is a complication of advanced breast and prostate cancer. Tumor-secreted Dickkopf homolog 1 (DKK1), an inhibitor of canonical Wnt signaling and osteoblast differentiation, was proposed to regulate the osteoblastic response to metastatic cancer in bone. The objectives of this study were to compare DKK1 expression with the in vivo osteoblastic response in a panel of breast and prostate cancer cell lines, and to discover mechanisms that regulate cancer DKK1 expression. DKK1 expression was highest in MDA-MB-231 and PC3 cells that produce osteolytic lesions, and hence a suppressed osteoblastic response, in animal models of bone metastasis. LnCaP, C4-2B, LuCaP23.1, T47D, ZR-75-1, MCF-7, ARCaP and ARCaPM cancer cells that generate osteoblastic, mixed or no bone lesions had the lowest DKK1 expression. The cell lines with negligible expression, LnCaP, C4-2B and T47D, exhibited methylation of the DKK1 promoter. Canonical Wnt signaling activity was then determined and found in all cell lines tested, even in the MDA-MB-231 and PC3 cell lines despite sizeable amounts of DKK1 protein expression expected to block canonical Wnt signaling. A mechanism of DKK1 resistance in the osteolytic cell lines was investigated and determined to be at least partially due to down-regulation of the DKK1 receptors Kremen1 and Kremen2 in the MDA-MB-231 and PC3 cell lines. Combined DKK1 and Kremen expression in cancer cells may serve as predictive markers of the osteoblastic response of breast and prostate cancer bone metastasis.

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“…3) shows that this ability is regulated through multiple extrinsic (WNT, TGFb/Activin and BMP signaling, PDGF) and intrinsic factors (Oct4, Sox2, and Nanog). b-catenin-dependent Wnt signaling is associated with stem cell maintenance [41] and has been showed to be overexpressed in TNBC [42]. WNT binding to the frizzled receptors leads to CTNN-b accumulation and translocation to the nucleus where it activates TCF/LEF-mediated gene transcription of target genes that signal differentiation (Fig.…”

Section: Discussionmentioning

confidence: 97%

Regulation of stem cells-related signaling pathways in response to doxorubicin treatment in Hs578T triple-negative breast cancer cells

et al. 2015

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Different molecular changes have been previously associated with therapeutic response and recurrent disease, however, the detailed mechanism of action in triple-negative breast cancer subtype remains elusive. In this study, we investigated the cellular and molecular signaling of two claudin-low triple-negative breast cancer cells to doxorubicin and docetaxel treatment. Whole human transcriptomic evaluation was used to identify the subsequent changes in gene expression, while biological effects were measured by means of proliferation and anchorage-independent growth assays. Microarray analysis revealed changes in stem cell-related signaling pathways, suggesting that doxorubicin treatment affects the balance between self-renewal and differentiation. While the treatment reduced the proliferation, aggregation and mammosphere forming ability of stem-like cells derived from Hs578T cell line, stem-like cells derived from MDA-MB-231 cells were not significantly affected. Our results suggest that claudin-low triple-negative breast cancer cells might predominantly alter stem cell-related signaling pathways to promote stem-like cells activity as an innate resistance mechanism to doxorubicin treatment.

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Mammary stem cells and cancer: roles of Wnt signaling in plain view

Cited by 11 publications

References 14 publications

Parity induces differentiation and reduces Wnt/Notch signaling ratio and proliferation potential of basal stem/progenitor cells isolated from mouse mammary epithelium

Parity induces differentiation and reduces Wnt/Notch signaling ratio and proliferation potential of basal stem/progenitor cells isolated from mouse mammary epithelium

DKK1 and Kremen Expression Predicts the Osteoblastic Response to Bone Metastasis

Regulation of stem cells-related signaling pathways in response to doxorubicin treatment in Hs578T triple-negative breast cancer cells

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