Targeted Disruption of the IGF-I Receptor Gene Decreases Cellular Proliferation in Mammary Terminal End Buds

Bonnette, Sharon

doi:10.1210/en.142.11.4937

Cited by 49 publications

(47 citation statements)

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“…Loss of IGF-I or IGF-IR expression in the mammary gland has been shown to result in a decrease in the number of TEBs, ductal branch points and ductal elongation (Ruan and Kleinberg, 1999;Bonnette and Hadsell, 2001;Richards et al, 2004). Delayed ductal growth and a reduction in TEB number was also observed in a transgenic mouse model overexpressing a constitutively activated IGF-IR in the mammary epithjleium (Carboni et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Transgenic overexpression of IGF-IR disrupts mammary ductal morphogenesis and induces tumor formation

et al. 2006

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Overexpression and hyperactivation of the type I insulinlike growth factor receptor (IGF-IR) has been observed in human breast tumor biopsies. In addition, in vitro studies indicate that overexpression of IGF-IR is sufficient to transform cells such as mouse embryo fibroblasts and this receptor promotes proliferation and survival in breast cancer cell lines. To fully understand the function of the IGF-IR in tumor initiation and progression, transgenic mice containing human IGF-IR under a doxycyclineinducible MMTV promoter system were generated. Administration of 2 mg/ml doxycycline in the animals' water supply beginning at 21 days of age resulted in elevated levels of IGF-IR in mammary epithelial cells as detected by Western blotting and immunohistochemistry. Whole mount analysis of 55-day-old mouse mammary glands revealed that IGF-IR overexpression significantly impaired ductal elongation. Moreover, histological analyses revealed multiple hyperplasic lesions in the mammary glands of these 55-day-old mice. The formation of palpable mammary tumors was evident at approximately 2 months of age and was associated with increased levels of IGF-IR signaling molecules including phosphorylated Akt, Erk1/Erk2 and STAT3. Therefore, these transgenic mice provide evidence that IGF-IR overexpression is sufficient to induce mammary epithelial hyperplasia and tumor formation in vivo and provide a model to further understand the function of IGF-IR in mammary epithelial transformation.

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Section: Discussionmentioning

confidence: 99%

Transgenic overexpression of IGF-IR disrupts mammary ductal morphogenesis and induces tumor formation

et al. 2006

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“…3G). Interestingly, Igf1, another growth factor that promotes mammary gland development (14), was also up-regulated at the mRNA level in Spry1KO fibroblasts (Fig. 3G).…”

Section: Mammary Stromal Fibroblasts Lacking Spry1 Promote Epithelialmentioning

confidence: 93%

“…Stromal cells produce several paracrine factors, including fibroblast growth factors (FGFs) and insulin-like growth factor (IGF) that activate receptor tyrosine kinases (RTK) (11,12). For example, a reduction in FGF signaling due to loss of FGF10 or its receptor FGF receptor 1/2 (FGFR1/2), or reduced IGF signaling, leads to stunted epithelial branching (13)(14)(15)(16). By contrast, excessive FGF signaling due to overactive FGF ligand or receptor causes breast tumorigenesis in mouse models (17)(18)(19).…”

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confidence: 99%

SPRY1 regulates mammary epithelial morphogenesis by modulating EGFR-dependent stromal paracrine signaling and ECM remodeling

Koledová

Zhang

Streuli

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The role of the local microenvironment in influencing cell behavior is central to both normal development and cancer formation. Here, we show that sprouty 1 (SPRY1) modulates the microenvironment to enable proper mammary branching morphogenesis. This process occurs through negative regulation of epidermal growth factor receptor (EGFR) signaling in mammary stroma. Loss of SPRY1 resulted in up-regulation of EGFR-extracellular signal-regulated kinase (ERK) signaling in response to amphiregulin and transforming growth factor alpha stimulation. Consequently, stromal paracrine signaling and ECM remodeling is augmented, leading to increased epithelial branching in the mutant gland. By contrast, down-regulation of EGFR-ERK signaling due to gain of Sprouty function in the stroma led to stunted epithelial branching. Taken together, our results show that modulation of stromal paracrine signaling and ECM remodeling by SPRY1 regulates mammary epithelial morphogenesis during postnatal development.branching morphogenesis | FGF signaling | EGF signaling | epithelial-stromal interactions | stromal microenvironment A central theme in developmental and cancer biology research is to understand the mechanisms by which the local microenvironment, or niche, influences fundamental aspects of cell and tissue behavior during organ formation and function (1). The importance of mesenchyme, as the embryonic niche, in determining organ identity and fate of the epithelium was demonstrated long ago by classic embryological studies (2, 3). More recent studies have shown, however, that postnatal stroma, a derivative of embryonic mesenchyme, is essential for maintenance of cell fate and differentiation status in adult life (4, 5). Indeed, abnormal stroma can lead to the formation of a cancer microenvironment, and it plays a causative role during tumor onset and progression (1, 6). As such, understanding postnatal stromal biology and the mechanism by which its deregulation may promote tumorigenesis is of key importance.The mouse mammary gland is a powerful model for understanding the genetic and cellular basis of stromal biology (7). The observation that epithelial branching of the mammary gland persists for many weeks after birth has made amenable the detection of stromal influences on epithelial invasion and patterning (8, 9). Indeed, postnatal mammary stroma is composed of many cell types, including periductal fibroblasts and white adipocytes, endothelial cells, nerve cells, and a variety of infiltrating immune cells, including macrophages and eosinophils, which play an important role in postnatal branching (10).Mammary stroma regulates epithelial branching by at least two mechanisms. Stromal cells produce several paracrine factors, including fibroblast growth factors (FGFs) and insulin-like growth factor (IGF) that activate receptor tyrosine kinases (RTK) (11, 12). For example, a reduction in FGF signaling due to loss of FGF10 or its receptor FGF receptor 1/2 (FGFR1/2), or reduced IGF signaling, leads to stunted epithelial branching (13-16). B...

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“…On the other hand, mammary branching is impeded in global IGF1 knockout mice lacking both systemic and local IGF1 production. Furthermore, IGF1 receptor (IGF1R) deficient mammary transplants exhibit reduced growth in surgically cleared wild-type fat pads [59], suggesting that IGF1R is required in the epithelium, since it was otherwise expressed in the host fat pads. By comparison, similar experiments show that the GH receptor is required in the stroma [57].…”

Section: What Cues Act Upstream Of the Adam17-areg-egfr Axis?mentioning

confidence: 99%

The ADAM17–amphiregulin–EGFR Axis in Mammary Development and Cancer

Sternlicht

Sunnarborg

2008

J Mammary Gland Biol Neoplasia

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In order to fulfill its function of producing and delivering sufficient milk to newborn mammalian offspring, the mammary gland first has to form an extensive ductal network. As in all phases of mammary development, hormonal cues elicit local intra-and inter-cellular signaling cascades that regulate ductal growth and differentiation. Among other things, ductal development requires the epidermal growth factor receptor (EGFR), its ligand amphiregulin (AREG), and the transmembrane metalloproteinase AD-AM17, which can cleave and release AREG from the cell surface so that it may interact with its receptor. Tissue recombination and transplantation studies demonstrate that EGFR phosphorylation and ductal development proceed only when ADAM17 and AREG are expressed on mammary epithelial cells and EGFR is present on stromal cells, and that local administration of soluble AREG can rescue the development of ADAM17-deficient transplants. Thus proper mammary morphogenesis requires the ADAM17-mediated release of AREG from ductal epithelial cells, the subsequent activation of EGFR on stromal cells, and EGFR-dependent stromal responses that in return elicit a new set of epithelial responses, all culminating in the formation of a fully functional ductal tree. This, however, raises new issues concerning what may act upstream, downstream or in parallel with the ADAM17-AREG-EGFR axis, how it may become hijacked or corrupted during the onset and evolution of cancer, and how such ill effects may be confronted.

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Targeted Disruption of the IGF-I Receptor Gene Decreases Cellular Proliferation in Mammary Terminal End Buds

Cited by 49 publications

References 0 publications

Transgenic overexpression of IGF-IR disrupts mammary ductal morphogenesis and induces tumor formation

Transgenic overexpression of IGF-IR disrupts mammary ductal morphogenesis and induces tumor formation

SPRY1 regulates mammary epithelial morphogenesis by modulating EGFR-dependent stromal paracrine signaling and ECM remodeling

The ADAM17–amphiregulin–EGFR Axis in Mammary Development and Cancer

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