Human mammary cancer progression model recapitulates methylation events associated with breast premalignancy

Dumont, Nancy; Crawford, Yongping; Sigaroudinia, Mahvash; S, Nagrani; Wilson, Mark; Buehring, Gertrude Case; Turashvili, Gulisa; Aparicio, Samuel; Gauthier, Mona L.; Fordyce, Colleen; McDermott, Kimberly M.; Tlsty, Thea D.

doi:10.1186/bcr2457

Cited by 28 publications

(29 citation statements)

References 37 publications

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“…These changes may be partially explained by alterations in the expression of genes critical for mammary gland development and by an increase in the number of mammosphere forming cells. Previously, it has been demonstrated that suppression of SFRP1 expression is an early change in human premalignant breast lesions [21]. Taken together, our study indicates that the SFRP1 gene is critical for maintaining proper mammary gland development, that reduced levels of SFRP1 results in hyperplastic lesions, and its loss may be a critical event in cancer initiation.…”

Section: Discussionsupporting

confidence: 71%

Loss of sfrp1 promotes ductal branching in the murine mammary gland

Gauger

Shimono²,

Crisi

et al. 2012

BMC Dev Biol

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BackgroundSecreted frizzled-related proteins (SFRPs) are a family of proteins that block the Wnt signaling pathway and loss of SFRP1 expression is found in breast cancer along with a multitude of other human cancers. Activated Wnt signaling leads to inappropriate mammary gland development and mammary tumorigenesis in mice. When SFRP1 is knocked down in immortalized non-malignant mammary epithelial cells, the cells exhibit a malignant phenotype which resembles the characteristics observed in metastatic breast cancer stem-like cells. However, the effects of SFRP1 loss on mammary gland development in vivo are yet to be elucidated. The work described here was initiated to investigate the role of SFRP1 in mammary gland development and whether SFRP1−/− mice exhibit changes in mammary gland morphology and cell signaling pathways shown to be associated with SFRP1 loss in vitro.Results10 week old nulliparous SFRP1−/− mammary glands exhibited branching with clear lobulo-alveolar development, which normally only occurs in hormonally stimulated mid-pregnant wt mammary glands. Explant cultures of SFRP1−/− mammary glands display increased levels of a well known Wnt signaling target gene, Axin2. Histomorphologic evaluation of virgin glands revealed that by 10 weeks of age, the duct profile is markedly altered in SFRP1−/− mice showing a significantly higher density of ducts with distinct alveoli present throughout the mammary gland, and with focal ductal epithelial hyperplasia. These findings persist as the mice age and are evident at 23 weeks of age. Changes in gene expression, including c-Myc, TGFβ-2, Wnt4, RANKL, and Rspo2 early in mammary gland development are consistent with the excessive hyper branching phenotype. Finally, we found that loss of SFRP1 significantly increases the number of mammary epithelial cells capable of mammosphere formation.ConclusionsOur study indicates that SFRP1 gene is critical for maintaining proper mammary gland development, and that reduced levels of SFRP1 results in hyperplastic lesions and its loss may be a critical event in cancer initiation.

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Section: Discussionsupporting

confidence: 71%

Loss of sfrp1 promotes ductal branching in the murine mammary gland

Gauger

Shimono²,

Crisi

et al. 2012

BMC Dev Biol

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“…Previously, it has been demonstrated that suppression of SFRP1 expression is an early change in human premalignant breast lesions [58] and loss of Sfrp1 in the mouse mammary gland results in hyperplastic lesions [36]. In this study we clearly demonstrate that the mammary glands of Sfrp1 -/- mice exhibit enhanced macrophage infiltration (Figure 5A;Figure S5).…”

Section: Discussionsupporting

confidence: 71%

Mice Deficient in Sfrp1 Exhibit Increased Adiposity, Dysregulated Glucose Metabolism, and Enhanced Macrophage Infiltration

et al. 2013

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The molecular mechanisms involved in the development of obesity and related complications remain unclear. Wnt signaling plays an important role in preadipocyte differentiation and adipogenesis. The expression of a Wnt antagonist, secreted frizzled related protein 1 (SFRP1), is increased in response to initial weight gain, then levels are reduced under conditions of extreme obesity in both humans and animals. Here we report that loss of Sfrp1 exacerbates weight gain, glucose homeostasis and inflammation in mice in response to diet induced obesity (DIO). Sfrp1-/- mice fed a high fat diet (HFD) exhibited an increase in body mass accompanied by increases in body fat percentage, visceral white adipose tissue (WAT) mass, and adipocyte size. Moreover, Sfrp1 deficiency increases the mRNA levels of key de novo lipid synthesis genes (Fasn, Acaca, Acly, Elovl, Scd1) and the transcription factors that regulate their expression (Lxr-α, Srebp1, Chreb, and Nr1h3) in WAT. Fasting glucose levels are elevated, glucose clearance is impaired, hepatic gluconeogenesis regulators are aberrantly upregulated (G6pc and Pck1), and glucose transporters are repressed (Slc2a2 and Slc2a4) in Sfrp1-/- mice fed a HFD. Additionally, we observed increased steatosis in the livers of Sfrp1-/- mice. When there is an expansion of adipose tissue there is a sustained inflammatory response accompanied by adipokine dysregulation, which leads to chronic subclinical inflammation. Thus, we assessed the inflammatory state of different tissues and revealed that Sfrp1-/- mice fed a HFD exhibited increased macrophage infiltration and expression of pro-inflammatory markers including IL-6, Nmnat, Tgf-β2, and SerpinE1. Our findings demonstrate that the expression of Sfrp1 is a critical factor required for maintaining appropriate cellular signaling in response to the onset of obesity.

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“…Suppression of SFRP1 expression is also linked to early changes in human premalignant breast lesions (Dumont et al, 2009), and may represent a novel diagnostic marker in women thought to have atypical ductal hyperplasia and/or lobular carcinoma in situ. Nonetheless, whether SFRP1 loss is merely associated with breast cancer development or definitively leads to breast cancer development is unclear.…”

Section: Discussionmentioning

confidence: 99%

Tumour supressor secreted frizzled related protein 1 regulates p53‐mediated apoptosis

Gauger

Schneider

2013

Cell Biology International

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The most frequently occurring cancer in women, and the second leading cause of cancer death among women, is breast cancer. Cancer results from cellular mutations that enhance proliferation and decrease programmed cell death (apoptosis). Secreted frizzled-related proteins (SFRPs) are a family of proteins known for their ability to negatively modulate the Wnt signalling cascade. SFRP1 expression is lost in a multitude of cancers, including breast cancer, and SFRP1 down regulation reduces apoptosis in vitro but the mechanisms remain unclear, as also the effect of Sfrp1 deficiency on apoptosis on mammary epithelial cells in vivo. Our data show that mammary glands from Sfrp1(-/-) mice express significantly less Bcl2l11 (Bim) and Bax mRNA in response to DNA damage. The effect of Sfrp1 loss in reducing γ-irradiation induced apoptosis was examined by TUNEL staining and cleaved-caspase-3 immunostaining. The findings show that Sfrp1(-/-) mice have less DNA fragmentation, whilst caspase-3 expression is decreased, and that p53 expression is generally diminished. Recombinant SFRP1 could replace endogenous expression and elevate the levels of pro-apoptotic and p53-mediated gene expression (Bcl2l, Bax, Cdkn1a and Bbc3) in mammary epithelial cells derived from Sfrp1(-/-) mice. Thus Sfrp1 plays an important role in mediating mammary epithelial apoptotic response to DNA damage in vivo. The role SFRP1 plays in p53 target gene expression was also noted, which suggests that this pathway may be worth exploiting for novel therapies.

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Human mammary cancer progression model recapitulates methylation events associated with breast premalignancy

Cited by 28 publications

References 37 publications

Loss of sfrp1 promotes ductal branching in the murine mammary gland

Loss of sfrp1 promotes ductal branching in the murine mammary gland

Mice Deficient in Sfrp1 Exhibit Increased Adiposity, Dysregulated Glucose Metabolism, and Enhanced Macrophage Infiltration

Tumour supressor secreted frizzled related protein 1 regulates p53‐mediated apoptosis

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