Evidence that transgenes encoding components of the Wnt signaling pathway preferentially induce mammary cancers from progenitor cells

Li, Yang; Welm, Bryan E.; Podsypanina, Katrina; Huang, Shixia; Chamorro, Mario; Zhang, Xiaomei; Rowlands, Tracey; Egeblad, Mikala; Cowin, Pamela; Werb, Zena; Tan, Lee K.; Rosen, Jeffrey M.; Varmus, Harold

doi:10.1073/pnas.2136825100

Cited by 480 publications

(493 citation statements)

References 47 publications

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“…Additionally, b-catenin activity is capable of maintaining an undifferentiated state in teratomas, implying that b-catenin signaling may push germ cells towards a proliferative undifferentiated state (Kielman et al, 2002). This finding agrees with the work of many studies that uncovered a role for b-catenin in stem cell maintenance (Li et al, 2003;Willert et al, 2003;Liu et al, 2004;Sato et al, 2004).…”

Section: Discussionsupporting

confidence: 87%

“…Similar findings were found in human embryonic stem cells where inhibition of GSK3b and subsequent b-catenin stabilization maintained the pluripotency of the cells in culture (Sato et al, 2004). During Wnt-induced transformation of mammary tissue this link to stem cell renewal is thought to result in preferential accumulation and induction of cancer from mammary progenitor cells (Li et al, 2003). Taken together, these findings imply that Wnt/b-catenin signaling is an important normal process in the proliferation and renewal of stem cells and that aberrant b-catenin regulation may simulate a stem cell-like proliferation, leading to uncontrolled proliferation and tumor formation.…”

supporting

confidence: 72%

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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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Section: Discussionsupporting

confidence: 87%

supporting

confidence: 72%

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

2006

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“…This transgenes appears to cause expansion of mammary progenitor cells, since there is a significant increase in cells expressing putative progenitor cell markers (such as Sca-1 and keratin 6) and cells effluxing fluorescent Hoechst 33342 dye -the dye-excluding property has been associated with stem cells in the hematopoietic system (Goodell et al, 1996;Li Y et al, 2003;Liu et al, 2004). The resulting tumors in MMTV-Wnt-1 TG mice also seem to arise from progenitor cells because the tumor cells also express Sca-1 and keratin 6, and because they contain heterogeneous tumor cells that share a common genetic mutation in Pten, implying a common progenitor (Cui and Donehower, 2000;Rosner et al, 2002;Li Y et al, 2003;Henry et al, 2004;Liu et al, 2004).…”

Section: Introductionmentioning

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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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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“…Since a variety of oncogenes such as TGFa and Wnt1 act as autocrine as well as paracrine growth factors (Brisken et al, 2000;Kisseberth and Sandgren, 2004), it would be incorrect to assume that PI-MECs are the sole targets for cellular transformation in all MMTV-LTR-based tumor models. In addition, it was recently suggested that the MMTV-wnt1 oncogene targets undifferentiated progenitors or mammary stem cells (Li et al, 2003;Liu et al, 2004). This could be a reason why MMTV-wnt1 mice exhibit a greater variety of histopathologically distinct lesions compared to the MMTV-neu model (Cardiff et al, 2000).…”

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confidence: 99%

Parity-induced mammary epithelial cells facilitate tumorigenesis in MMTV-neu transgenic mice

et al. 2004

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Using a Cre-lox-based genetic labeling technique, we have recently discovered a parity-induced mammary epithelial subtype that is abundant in nonlactating and nonpregnant, parous females. These mammary epithelial cells serve as alveolar progenitors in subsequent pregnancies, and transplantation studies revealed that they possess features of multipotent progenitors such as self-renewal and the capability to contribute to ductal and alveolar morphogenesis. Here, we report that these cells are the cellular targets for transformation in MMTV-neu transgenic mice that exhibit accelerated mammary tumorigenesis in multiparous animals. The selective ablation of this epithelial subtype reduces the onset of tumorigenesis in multiparous MMTV-neu transgenics. There is, however, experimental evidence to suggest that parity-induced mammary epithelial cells may not be the only cellular targets in other MMTV-promoter-based transgenic strains. In particular, the heterogeneous MMTV-wnt1 lesions predominantly express the ductal differentiation marker Nkcc1 that is absent in MMTV-neu-derived tumors. Our observations support the idea that tumors originate from distinctly different epithelial subtypes in selected MMTV-promoter-driven cancer models and that diverse oncogenes might exert discrete effects on particular mammary epithelial subtypes.

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Evidence that transgenes encoding components of the Wnt signaling pathway preferentially induce mammary cancers from progenitor cells

Cited by 480 publications

References 47 publications

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

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

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

Parity-induced mammary epithelial cells facilitate tumorigenesis in MMTV-neu transgenic mice

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