Wnt signaling and mammary stem cells

Alexander, Caroline M.

doi:10.1016/bs.vh.2021.02.001

Cited by 4 publications

(1 citation statement)

References 127 publications

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“…Among these other types is breast cancer, which represents a different cancer type in which the steroid hormone receptors ER and PR play a crucial role in stratifying therapeutic treatment options, reflecting the instrumental role of hormonal regulation in the mammary epithelium. Hence, in the normal mammary gland, upstream steroid hormone signals are instructive in regulating mammary stem cell dynamics, and Wnt/β‐catenin signaling also plays an important stem cell regulatory role [ 4 , 15 , 16 , 17 ]. Importantly, mouse studies have indicated that the dictating role of upstream steroid hormone signals is executed through a collaborative Rspo1–Wnt4 signaling axis that potentiates Wnt/β‐catenin signaling and stimulates self‐renewal of mammary stem cells in the normal mammary gland [ 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

R‐spondin‐3 is an oncogenic driver of poorly differentiated invasive breast cancer

Steege

Boer

Timmer

et al. 2022

The Journal of Pathology

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R‐spondins (RSPOs) are influential signaling molecules that promote the Wnt/β‐catenin pathway and self‐renewal of stem cells. Currently, RSPOs are emerging as clinically relevant oncogenes, being linked to cancer development in multiple organs. Although this has instigated the rapid development and testing of therapeutic antibodies targeting RSPOs, functional evidence that RSPO causally drives cancer has focused primarily on the intestinal tract. Here, we assess the oncogenic capacity of RSPO in breast cancer in a direct fashion by generating and characterizing a novel mouse model with conditional Rspo3 expression in the mammary gland. We also address the prevalence of RSPO gene alterations in breast cancer patients. We found that a quarter of breast cancer patients harbor RSPO2/RSPO3 copy number amplifications, which are associated with lack of steroid hormone receptor expression and reduced patient survival. Foremost, we demonstrate the causal oncogenic capacity of RSPO3 in the breast, as conditional Rspo3 overexpression consistently drives the development of mammary adenocarcinomas in our novel Rspo3 breast cancer model. RSPO3‐driven mammary tumors typically show poor differentiation, areas of epithelial‐to‐mesenchymal transition, and metastatic potential. Given the reported interplay in the Wnt/β‐catenin pathway, we comparatively analyzed RSPO3‐driven mouse mammary tumors versus classical WNT1‐driven analogues. This revealed that RSPO3‐driven tumors are distinct, as the poorly differentiated tumor morphology and metastatic potential were observed in RSPO3‐driven tumorigenesis exclusively, further substantiated by differentiating gene expression profiles. Co‐expression of Rspo3 and Wnt1 transduced mammary tumors with a mixed phenotype harboring morphological features characteristic of both transgenes. In summary, we report that a quarter of breast cancer patients harbor RSPO2/RSPO3 copy number gains, and these patients have a worse prognosis, whilst providing in vivo evidence that RSPO3 drives poorly differentiated invasive breast cancer in mice. Herewith, we establish RSPO3 as a driver of breast cancer with clinical relevance, proposing RSPO3 as a novel candidate target for therapy in breast cancer. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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Section: Introductionmentioning

confidence: 99%

R‐spondin‐3 is an oncogenic driver of poorly differentiated invasive breast cancer

Steege

Boer

Timmer

et al. 2022

The Journal of Pathology

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Lithium Chloride Promotes Milk Protein and Fat Synthesis in Bovine Mammary Epithelial Cells via HIF-1α and β-Catenin Signaling Pathways

Zong

Shen

Liu

et al. 2022

Biol Trace Elem Res

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Functional ProTracer identifies patterns of cell proliferation in tissues and underlying regulatory mechanisms

et al. 2023

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A genetic system, ProTracer, has been recently developed to record cell proliferation in vivo. However, the ProTracer is initiated by an infrequently used recombinase Dre, which limits its broad application for functional studies employing floxed gene alleles. Here we generated Cre-activated functional ProTracer (fProTracer) mice, which enable simultaneous recording of cell proliferation and tissue-specific gene deletion, facilitating broad functional analysis of cell proliferation by any Cre driver.

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Wnt signaling and mammary stem cells

Cited by 4 publications

References 127 publications

R‐spondin‐3 is an oncogenic driver of poorly differentiated invasive breast cancer

R‐spondin‐3 is an oncogenic driver of poorly differentiated invasive breast cancer

Lithium Chloride Promotes Milk Protein and Fat Synthesis in Bovine Mammary Epithelial Cells via HIF-1α and β-Catenin Signaling Pathways

Functional ProTracer identifies patterns of cell proliferation in tissues and underlying regulatory mechanisms

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