Cooperative induction of mammary tumorigenesis by TGFα and Wnts

Schroeder, Joyce A.; Troyer, Kelly L.; Lee, David C

doi:10.1038/sj.onc.1203652

Cited by 29 publications

(15 citation statements)

References 31 publications

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“…Wnt and EGFR signaling activities have important functional roles in a wide range of biological processes, from developmental fate decisions to neoplasia. These signaling pathways can act antagonistically as in Drosophila larval cuticle development (24) or cooperatively as in mouse mammary tumor formation (25). Civenni et al have reported that Wnt conditioned medium can activate the EGFR by a metalloprotease-dependent release of EGFR ligands in a manner analogous to GPCR transactivation of the EGFR (26,27).…”

Section: Discussionmentioning

confidence: 99%

Myristoylated Naked2 escorts transforming growth factor α to the basolateral plasma membrane of polarized epithelial cells

Franklin²,

Graves‐Deal³

et al. 2004

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

114

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The epidermal growth factor receptor ligands transforming growth factor ␣ (TGF␣) and amphiregulin are delivered to the basolateral surface of polarized epithelial cells where they are cleaved by TACE͞ ADAM17. Basolateral sorting information resides in their cytoplasmic tail domains, but tail-interacting proteins required for basolateral trafficking have not been identified. Naked (NKD)1 and NKD2 are mammalian homologs of Drosophila Naked Cuticle, which negatively regulates canonical Wnt signaling by binding Dishevelled. We present evidence that NKD2, but not NKD1, binds to basolateral sorting motifs in the cytoplasmic tail of TGF␣. Processing and cell-surface delivery of TGF␣ are accelerated in NKD2-overexpressing Madin-Darby canine kidney cells. NKD2 is myristoylated on glycine, the second residue. On expression of myristoylation-defective (G2A) NKD2, neither NKD2 nor TGF␣ appears at the basolateral plasma membrane of polarized Madin-Darby canine kidney cells; however, membrane staining for TGF␣ is restored on silencing expression of this mutant NKD2. Amphiregulin does not interact with NKD2 and retains its basolateral localization in G2A-NKD2-expressing cells, as do Na ؉ , K ؉ ATPase ␣1 and E-cadherin. These data identify an unexpected function for NKD2, i.e., myristoylation-dependent escort of TGF␣ to the basolateral plasma membrane of polarized epithelial cells.

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Section: Discussionmentioning

confidence: 99%

Myristoylated Naked2 escorts transforming growth factor α to the basolateral plasma membrane of polarized epithelial cells

Franklin²,

Graves‐Deal³

et al. 2004

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

114

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“…Glands-Previous studies have demonstrated a functional relationship between ␤-catenin and EGFR in tumor progression (9,16). We therefore analyzed our tumor and mammary gland samples to determine if the 180-kDa kinase we had detected immunoprecipitating with ␤-catenin ( Fig.…”

Section: Egfr and C-neu Associate With ␤-Catenin In Tumors But Not Nomentioning

confidence: 99%

“…Is Tyrosine-phosphorylated in MMTV-Wnt-1 Tumors-EGFR-induced tumor formation in the mammary gland is promoted by cooperative events with Wnt-mediated signaling, since both Wnt-1 and Wnt-3 were found to be up-regulated in tumor samples from WAP-TGF␣ transgenic animals (9). To directly examine the role of EGFR signaling in Wnt-1-mediated tumorigenesis, we utilized the MMTV-Wnt-1 transgenic mouse (19).…”

Section: ␤-Cateninmentioning

confidence: 99%

“…The development of transgenic lines targeting overexpression of either the ligands (3) or the receptors (5,6) to the mammary gland invariably results in tumorigenesis and has been useful in elucidating the involvement of other proteins in ErbB-related oncogenesis, such as c-Myc (7) and cyclin D1 (8). One such study utilized insertional mutagenesis of the WAP-transforming growth factor ␣ (TGF␣) model to identify genes able to synergize with EGFR activation in tumor progression (9). These studies resulted in the observation that Wnt-1 and Wnt-3 are up-regulated in this model of ErbB-induced tumorigenesis, indicating that these pathways may cooperate during transformation.…”

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confidence: 99%

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ErbB-β-Catenin Complexes Are Associated with Human Infiltrating Ductal Breast and Murine Mammary Tumor Virus (MMTV)-Wnt-1 and MMTV-c-Neu Transgenic Carcinomas

Schroeder¹,

Adriance²,

McConnell

et al. 2002

Journal of Biological Chemistry

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Simultaneous deregulation of both Wnt and ErbB growth factors has previously been shown to result in the cooperative induction of mammary gland tumors. Using the murine mammary tumor virus (MMTV)-Wnt-1 transgenic model of mammary carcinoma, we have identified an unvarying association between ␤-catenin and epidermal growth factor receptor/c-Neu (ErbB1/ErbB2) heterodimers in mammary gland tumors, indicating a requirement for ErbB signaling in Wnt-mediated tumorigenesis. Expansion of these observations to a second transgenic model, MMTV-c-Neu, demonstrated similar tumor-specific interactions, including an ErbB1 ligandinducible phosphorylation of both ␤-catenin and c-Neu. Direct relevance of these findings to human breast cancer was established upon examination of a set of human infiltrating ductal breast adenocarcinoma and lymph node metastasis tissues taken at surgery. These data revealed increased levels of ␤-catenin in tumors and metastases versus normal breast as well as an association between ␤-catenin and c-Neu that measurably occurs only in neoplasia, most strongly in metastatic lesions. These studies have identified a seemingly indispensable interaction between ␤-catenin and epidermal growth factor receptor/c-Neu heterodimers in Wnt-1-mediated breast tumorigenesis that may indicate a fundamental signaling event in human metastatic progression.The ErbB family of transmembrane receptor tyrosine kinases (ErbB1 or epidermal growth factor receptor (EGFR), 1 ErbB2 or Her2/c-Neu, ErbB3, and ErbB4) and ligands (including EGF-like ligands and neuregulin-like ligands) have been consistently implicated in mammary gland tumorigenesis in both humans and rodents (1-3). The ErbB receptors are activated by the binding of cognate ligands, resulting in homo-and heterodimer receptor formation and subsequent phosphorylation of a wide variety of cellular substrates (i.e. mitogen-activated protein kinase, signal transducers and activators of transcription, phospholipase C␥, c-src, etc. (4)), most often leading to increased cellular mitogenesis. The development of transgenic lines targeting overexpression of either the ligands (3) or the receptors (5, 6) to the mammary gland invariably results in tumorigenesis and has been useful in elucidating the involvement of other proteins in ErbB-related oncogenesis, such as c-Myc (7) and cyclin D1 (8). One such study utilized insertional mutagenesis of the WAP-transforming growth factor ␣ (TGF␣) model to identify genes able to synergize with EGFR activation in tumor progression (9). These studies resulted in the observation that Wnt-1 and Wnt-3 are up-regulated in this model of ErbB-induced tumorigenesis, indicating that these pathways may cooperate during transformation.The Wnts are a family of secreted proteins whose overexpression results in the accumulation of ␤-catenin, a protein involved in both cellular adhesion (as a critical component of the E-cadherin-actin complex found at adherens junctions) and oncogenesis (10, 11). Binding of the soluble Wnt protein to the Frizzled receptor r...

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“…When wnt-1 or int-2 was targeted to the mammary gland of transgenic mice, wnt-1 was highly tumorigenic in females whereas int-2 was weakly tumorigenic; the two oncogenes acted synergistically in doubly transgenic animals (Kwan et al, 1992). It has been shown recently that wnt-1 can also cooperate with TGFa in transgenic animals (Schroeder et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Wnt-1 and int-2 mammary oncogene effects on the β-catenin pathway in immortalized mouse mammary epithelial cells are not sufficient for tumorigenesis

et al. 2001

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Development of strategies for prevention of breast cancer development requires an understanding of the eects of mammary oncogenes on mammary cells at early stages in neoplastic transformation. As mammary oncogenes wnt-1 and int-2 aect dierent signal transduction pathways, we investigated their eects on established mouse mammary epithelial cell lines (MMECLs) re¯ecting early stages in tumorigenesis. Normal interactions between b-catenin and E-cadherin were abrogated in all three immortalized MMECLs and the cells lacked b-catenin-mediated transactivation activity, detectable using a reporter assay, suggesting that alterations in cell adhesion may be very early events in mammary tumorigenesis. Immortalized FSK4 and EL12 cells and hyperplastic TM3 cells were stably transfected with expression vectors encoding wnt-1 or int-2 or the control vector, and drug-selected pooled cells from each line were con®rmed by reverse transcription-polymerase chain reaction to express the transfected oncogene; this expression persisted in the cells analysed in vitro and in vivo. Resultant phenotypic changes depended both on the oncogene and the target mammary cell line. In FSK4 cells, expression of wnt-1 or int-2 resulted in proliferative changes in vitro, including reduced contact inhibition, increased b-catenin expression, and decreased p53 transcriptional activity, but neither oncogene conferred upon those cells the ability to produce tumors in vivo. EL12 cells were highly refractory to the eects of both oncogenes, with the only measurable changes being increased E-cadherin levels induced by both oncogenes and increased proliferation of the int-2-transfected cells in the absence of serum. Parental TM3 cells were phenotypically similar to wnt-1-or int-2-transfected FSK4 cells and displayed an increased rate of proliferation in vitro and markedly increased tumorigenicity in vivo following transfection with int-2 but not with wnt-1. These results suggest that wnt-1 signaling is redundant in the hyperplastic TM3 cells and indicate that wnt-1-induced eects in the immortalized FSK4 and EL12 cells were not sucient to mediate a tumorigenic phenotype. This study showed that the wnt-1 and int-2 oncogenes have similar but distinguishable eects on immortalized MMECLs and that the genetic background of the mammary cells greatly in¯uences the consequences of oncogene expression at early stages of cell transformation. Oncogene (2001) 20, 7645 ± 7657.

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Cooperative induction of mammary tumorigenesis by TGFα and Wnts

Cited by 29 publications

References 31 publications

Myristoylated Naked2 escorts transforming growth factor α to the basolateral plasma membrane of polarized epithelial cells

Myristoylated Naked2 escorts transforming growth factor α to the basolateral plasma membrane of polarized epithelial cells

ErbB-β-Catenin Complexes Are Associated with Human Infiltrating Ductal Breast and Murine Mammary Tumor Virus (MMTV)-Wnt-1 and MMTV-c-Neu Transgenic Carcinomas

Wnt-1 and int-2 mammary oncogene effects on the β-catenin pathway in immortalized mouse mammary epithelial cells are not sufficient for tumorigenesis

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