Mammary tumor suppression by transforming growth factor beta 1 transgene expression.

Pierce, Donald F.; Gorska, Agnieszka E.; Chytil, Anna; Meise, Katherine S.; Page, David L.; Coffey, Robert J.; Moses, Harold L.

doi:10.1073/pnas.92.10.4254

Cited by 267 publications

(180 citation statements)

References 32 publications

(29 reference statements)

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“…This factor driven by the MMTV-LTR promoter was able to inhibit tumor development when crossed with MMTV-LTR TGF␣ transgenic mice that developed early alveolar hyperplasias that progress to mammary carcinomas. 6,19 MMTV LTR-TGF␤1 was also able to inhibit mammary tumorigenesis in virgin animals treated with DMBA. 6 We believe that these neoplasias arise from non-secretory cells where MMTV-LTR promoter can be active.…”

Section: Discussionmentioning

confidence: 95%

“…6,19 MMTV LTR-TGF␤1 was also able to inhibit mammary tumorigenesis in virgin animals treated with DMBA. 6 We believe that these neoplasias arise from non-secretory cells where MMTV-LTR promoter can be active. Another example of the ability of TGF␤1 in inhibiting mammary tumor development was observed in bitransgenic WAP-TGF␤1 x Met-TGF␣ mice.…”

Section: Discussionmentioning

confidence: 95%

“…5 In neither WAP nor MMTV driven TGF␤1 transgenic animals, mammary carcinomas have been reported. 4,6 In particular, no mammary tumors were observed in 20 WAP-TGF␤1 females maintained as breeders in our colony for over 2 years. In this case, the average age of death was 22.0 months (Smith, unpublished data).…”

mentioning

confidence: 76%

“…On the contrary, this factor showed mammary tumor suppressor activity in both TGF␤1 transgenic models when crossbred with TGF␣ transgenic or in MMTV-TGF␤1 transgenic DMBA treated mice. 6,7 Mouse mammary tumor virus (MMTV) is a type B retrovirus that causes mammary tumors in susceptible mice. MMTV is transmitted either horizontally as a milk-borne exogenous virus or vertically as a germ-line integrated provirus.…”

Section: Abstract: Mammary Tumor; Mmtv; Tgf␤1; Stem Cellsmentioning

confidence: 99%

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Impairment of mammary lobular development induced by expression of TGF?1 under the control of WAP promoter does not suppress tumorigenesis in MMTV-infected transgenic mice

et al. 2001

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It has previously been shown that transgenic female mice expressing TGF␤1 under control of regulatory elements of the whey-acidic protein (WAP) gene were unable to lactate. This was due to the increased apoptosis of the cells committed to the lobular-lactogenic phenotype. Our goal was to determine whether the expression of WAP-TGF␤1 transgene could inhibit MMTV (mouse mammary tumor virus) tumorigenic activity in the mammary gland. It is well known that the infection with this virus produces focal hyperplastic secretory nodules (HANs) and, some variants can also induce ductal pregnancy-dependent lesions (plaques). In either case, MMTV infection leads ultimately to the appearance of malignant mammary tumors. The results shown herein demonstrate that TGF␤1 expression in the secretory mammary epithelium does not suppress mammary tumorigenesis in MMTV infected mice. Although MMTV infected WAP-TGF␤1 transgenic females displayed a strong impairment of lobule-alveolar development, carcinogenesis induced by any of the four MMTV variants used herein proceeded unabated. WAP-TGF␤1 tumors that showed a strong expression at the WAP promoter, appeared later and grew more slowly than their wild-type counterparts. Transgenic females also had a lower incidence of HANs and plaques. Our study suggests that the epithelial target cells for tumorigenic mutations are probably progenitor cells that are not susceptible to the apoptotic effect of TGF␤1. Alternatively, their daughters cells that display the secretory phenotype and could be more involved in the formation of premalignant lesions continue to die due to the expression of the transgene. © 2001 Wiley-Liss, Inc. Key words: mammary tumor; MMTV; TGF␤1; stem cellsTransforming growth factor-␤1 is a member of a large superfamily of polypeptides and seems to affect many key events in normal growth and differentiation. 1,2 There is good evidence that members of the TGF␤1 gene family may indeed contribute essential signals for the development and secretory maturation of the mammary epithelium. An approach to TGF␤ function and mammary gland development has been the use of transgenic mice. TGF␤1 has been targeted to the mammary epithelium from different transcriptional promoters in two transgenic mouse models. In one, the mouse mammary tumor virus-long terminal repeat (MMTV-LTR) was used to promote expression of TGF␤1 in mammary epithelium. 3 In this biological model, a transient but distinct inhibition of mammary ductal extension and side branching was observed between 3 and 6 weeks of age; however subsequent development during pregnancy and lactation proceeded apparently unperturbed. In the second transgenic mouse model, TGF␤1 was expressed under the control of the whey acidic protein (WAP) promoter. This promoter is mammary epithelium-specific and most active during late pregnancy and lactation. In this model no inhibition of mammary ductal growth at puberty was observed. 4 With the onset of pregnancy, lobule-alveolar growth and development were impaired to the extent that lactation was...

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 95%

mentioning

confidence: 76%

Section: Abstract: Mammary Tumor; Mmtv; Tgf␤1; Stem Cellsmentioning

confidence: 99%

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Impairment of mammary lobular development induced by expression of TGF?1 under the control of WAP promoter does not suppress tumorigenesis in MMTV-infected transgenic mice

et al. 2001

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“…9 -11 Retroviruses carrying MMTV LTR-antisense c-myc effectively inhibit the growth of prostate cancer DU145 cells in vivo. 12 MMTV LTR transforming growth factor-␤ transgenic mice have mammary 13,14 and prostate 15 tissue hypoplasia.…”

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confidence: 99%

In vivo expression of prostate-specific adenoviral vectors in a canine model

et al. 1999

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The activity and expression of transgene ␤-galactosidase (lacZ) by replication-deficient adenoviral vectors (Ad-lacZ) containing prostate-specific promoters were compared using an in vivo canine model. The prostate tissue-specific promoters were prostate-specific antigen, probasin, and mouse mammary tumor virus long-terminal repeat, which were fused separately to an Escherichia coli lacZ gene. Dogs underwent laparotomy, and adenoviral vectors were delivered by direct intraprostatic injection. At 72 hours postinjection, the prostate and various other organs were harvested to evaluate the degree of prostate expression and dissemination of adenoviral vectors. Expression of lacZ in tissues was determined by 5-bromo-4-chloro-3-indolyl ␤-D-galactoside staining, ␤-galactosidase assay, and E. coli lacZ reverse transcriptase-polymerase chain reaction (PCR). The presence of adenoviral DNA sequences in canine tissues was determined by PCR using primers specific for the type 5 adenoviral genome. All three of the prostate-specific adenoviruses tested effectively expressed the lacZ gene in the canine prostate, but expression levels were lower than that of the control viral vector AdRSVlacZ following intraprostatic injection. By PCR, adenoviral vector DNA was detected in other organs and tissues, including the bladder and vas deferens. However, reverse transcriptase-PCR analysis revealed that prostate-specific Ad-lacZ vectors only transcribed lacZ mRNA in the prostate and not in nonprostatic tissues. Thus, these novel prostate-specific adenoviral vectors each have equal in vivo expression exclusively in the prostate and may potentially be used for prostate cancer gene therapy.

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Association Between the T29→C Polymorphism in the Transforming Growth Factor β1 Gene and Breast Cancer Among Elderly White Women

Ziv¹,

Cauley²,

Morin³

et al. 2001

JAMA

113

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Mammary tumor suppression by transforming growth factor beta 1 transgene expression.

Cited by 267 publications

References 32 publications

Impairment of mammary lobular development induced by expression of TGF?1 under the control of WAP promoter does not suppress tumorigenesis in MMTV-infected transgenic mice

Impairment of mammary lobular development induced by expression of TGF?1 under the control of WAP promoter does not suppress tumorigenesis in MMTV-infected transgenic mice

In vivo expression of prostate-specific adenoviral vectors in a canine model

Association Between the T29→C Polymorphism in the Transforming Growth Factor β1 Gene and Breast Cancer Among Elderly White Women

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