Δn89β-Catenin Induces Precocious Development, Differentiation, and Neoplasia in Mammary Gland

Imbert, Alexandra; Eelkema, Rachel; Jordan, Sara M.; Feiner, Helen; Cowin, Pamela

doi:10.1083/jcb.153.3.555

Cited by 203 publications

(224 citation statements)

References 67 publications

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“…TG expression of a stabilized mutant of b-catenin induces mammary tumors that bear similarities to tumors in Wnt-1 TG mice (Imbert et al, 2001;Michaelson and Leder, 2001). To our surprise, however, neither ER nor PR was detected in five tumors from b-catenin TG mice ( Figure 1a; see Discussion for possible explanations).…”

Section: Resultsmentioning

confidence: 99%

“…TG mice expressing Wnt-1 (Tsukamoto et al, 1988), the Neu protooncogene (Guy et al, 1992), an N-terminus-deleted, stabilized mutant of b-catenin (Imbert et al, 2001) and c-Myc (Stewart et al, 1984) have been described, as have mice harboring targeted inactivating mutations of Pten (Podsypanina et al, 1999) and p53 (Jacks et al, 1994). All TG mice were maintained on the FVB background, but Pten and p53 mutant mice were on mixed backgrounds of 129, FVB and C57/BL6.…”

Section: Micementioning

confidence: 99%

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Estrogen receptor positivity in mammary tumors of Wnt-1 transgenic mice is influenced by collaborating oncogenic mutations

et al. 2005

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The majority (75%) of human breast cancers express estrogen receptor (ER). Although ER-positive tumors usually respond to antiestrogen therapies, 30% of them do not. It is not known what controls the ER status of breast cancers or their responsiveness to antihormone interventions. In this report, we document that transgenic (TG) expression of Wnt-1 in mice induces ER-positive tumors. Loss of Pten or gain of Ras mutations during the evolution of tumors in Wnt-1 TG mice has no effect on the expression of ER, but overexpression of Neu or loss of p53 leads to ER-negative tumors. Thus, our results provide compelling evidence that expression of ER in breast cancer may be influenced by specific genetic changes that promote cancer progression. These findings constitute a first step to explore the molecular mechanisms leading to ER-positive or ER-negative mammary tumors. In addition, we find that ER-positive tumors arising in Wnt-1 TG mice are refractory to both ovariectomy and the ER antagonist tamoxifen, but lose ER expression with tamoxifen, suggesting that antiestrogen selects for ERnegative tumor cells and that the ER-positive cell fraction is dispensable for growth of these tumors. This is a first report of a mouse model of antiestrogen-resistant ERpositive breast cancers, and could provide a powerful tool to study the molecular mechanisms that control antiestrogen resistance.

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Section: Resultsmentioning

confidence: 99%

Section: Micementioning

confidence: 99%

Estrogen receptor positivity in mammary tumors of Wnt-1 transgenic mice is influenced by collaborating oncogenic mutations

et al. 2005

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“…E-cadherin is required for normal differentiation and survival of the epithelium. b-catenin/LEF signaling in the epithelium appears to be important to the formation of mammary buds, ductal extension, and alveologenesis, as well as maintenance of the normal adult mammary gland [Imbert et al, 2001;Hatsell et al, 2003]. Transmembrane P-cadherin expressed by the myoepithelium may play a role in regulating epithelial cell proliferation and invasion, whereas the role of sP-cadherin in the lactating gland or the suckling young is not understood.…”

Section: Cadherins and Catenins In The Normal Mammary Glandmentioning

confidence: 99%

Cadherins and the mammary gland

Knudsen

Wheelock

2005

J. Cell. Biochem.

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Cadherin cell-cell adhesion proteins are critical for the formation of tissues from single cells. E-and P-cadherin play important roles in the architecture and function of the normal mammary gland. In breast cancers, the expression, or lack thereof, of E-cadherin can differentiate tumor types, whereas the misexpression of either P-cadherin or N-cadherin can be a marker of poor prognosis or increased malignancy, respectively. Additional research is needed to more precisely define the roles of both classical and desmosomal cadherins and their downstream signaling events, in the development and malignant behavior of breast cancers. J. Cell. Classical and desmosomal cadherins mediate cell-cell adhesion and are members of the larger cadherin protein family. They are single-pass transmembrane proteins whose extracellular domain promotes cell-cell adhesion, while the intracellular domain interacts with cytoplasmic proteins, including the a-, b-, g-catenins (also known as plakoglobin) and p120 in the case of classical cadherins. a-and b-catenin (alternatively plakoglobin) link classical cadherins directly and indirectly to the actin cytoskeleton, whereas plakoglobin, desmoplakins, and plakophilins link desmosomal cadherins to the intermediate filament cytoskeleton. By virtue of their homophilic interaction and cell-type specific expression, the classical cadherins initiate cell-cell adhesion and promote cell sorting, whereas the desmosomal cadherins provide added strength to cell-cell interactions. The p120 catenin is thought to regulate clustering of classical cadherins in the plane of the membrane and to regulate the strength of cadherin cell adhesion in both positive and negative ways. In addition to playing important roles in cell adhesion, p120 and b-catenin interact with nuclear

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“…Furthermore, in lymph node negative breast tumors, the presence of high levels of b-catenin protein in combination with high levels of P53 protein correlated with poor survival of patients (Chung et al, 2004), indicating that b-catenin and P53 may have a combinatorial effect on tumor progression. In addition to the human data, studies using mouse models have demonstrated a role for b-catenin in initiating mammary tumors (Imbert et al, 2001;Michaelson and Leder, 2001).…”

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confidence: 99%

P53 levels determine outcome during β-catenin tumor initiation and metastasis in the mammary gland and male germ cells

2006

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b-catenin, an oncogene, and P53, a tumor suppressor, are common targets of mutation in human cancers. It has been observed that P53 is often inactivated in tumors involving b-catenin activation. In an attempt to model this situation in vivo, we crossed the previously characterized MMTV-DN-b-catenin mouse with the P53 knockout mouse. Female multiparous mice that carry the MMTV-DN-bcatenin transgene and that are heterozygous for P53 (Tg DN-bCat / þ , P53 þ /À) display an increased tumor burden (2.05 vs 1.31 tumors/animal), with a generally more advanced pathology, and increased metastatic rate (39 vs 0%) relative to transgenic female mice that are wild type for P53 (Tg DN-bCat / þ , P53 þ / þ ). These differences were not due to complete loss of P53 as only one of 21 tumors demonstrated loss of heterozygosity at the P53 locus. Furthermore, no mutations were present in tumors retaining a single wild-type allele. Tg DN-bCat / þ , P53À/À male mice developed testicular teratomas and survived an average of 65 days, whereas non-Tg DN-bCat , P53À/À males survived an average of 84 days. Sixty-two percent of Tg DN-bCat , P53À/À mice developed testicular teratomas, whereas only 10% of the non-Tg DN-bCat , P53À/À mice developed these tumors. These results indicate that the level of P53 and the tissue of origin are important factors in determining outcome of cancer caused by oncogene activation.

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Δn89β-Catenin Induces Precocious Development, Differentiation, and Neoplasia in Mammary Gland

Cited by 203 publications

References 67 publications

Estrogen receptor positivity in mammary tumors of Wnt-1 transgenic mice is influenced by collaborating oncogenic mutations

Estrogen receptor positivity in mammary tumors of Wnt-1 transgenic mice is influenced by collaborating oncogenic mutations

Cadherins and the mammary gland

P53 levels determine outcome during β-catenin tumor initiation and metastasis in the mammary gland and male germ cells

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