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Interactions between cells with distinct mutations in c-MYC and Pten in prostate cancer.

Kim J, Eltoum IE, Roh M, Wang J, Abdulkadir SA - PLoS Genet. (2009)

Bottom Line: These lesions were in all cases associated with loss of Pten protein expression from the wild type allele.We conclude that c-MYC overexpression and Pten deficiency cooperate to promote prostate tumorigenesis, but a p53-dependent apoptotic response may present a barrier to further progression.Our results highlight the utility of inducing mutations focally to model the competitive interactions between cell populations with distinct genetic alterations during tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA.

ABSTRACT
In human somatic tumorigenesis, mutations are thought to arise sporadically in individual cells surrounded by unaffected cells. This contrasts with most current transgenic models where mutations are induced synchronously in entire cell populations. Here we have modeled sporadic oncogene activation using a transgenic mouse in which c-MYC is focally activated in prostate luminal epithelial cells. Focal c-MYC expression resulted in mild pathology, but prostate-specific deletion of a single allele of the Pten tumor suppressor gene cooperated with c-MYC to induce high grade prostatic intraepithelial neoplasia (HGPIN)/cancer lesions. These lesions were in all cases associated with loss of Pten protein expression from the wild type allele. In the prostates of mice with concurrent homozygous deletion of Pten and focal c-MYC activation, double mutant (i.e. c-MYC+;Pten-) cells were of higher grade and proliferated faster than single mutant (Pten-) cells within the same glands. Consequently, double mutant cells outcompeted single mutant cells despite the presence of increased rates of apoptosis in the former. The p53 pathway was activated in Pten-deficient prostate cells and tissues, but c-MYC expression shifted the p53 response from senescence to apoptosis by repressing the p53 target gene p21(Cip1). We conclude that c-MYC overexpression and Pten deficiency cooperate to promote prostate tumorigenesis, but a p53-dependent apoptotic response may present a barrier to further progression. Our results highlight the utility of inducing mutations focally to model the competitive interactions between cell populations with distinct genetic alterations during tumorigenesis.

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c-MYC expression in PbCre4;Z-MYC mouse prostate is mosaic and uncoupled from androgen regulation.(A) LacZ stain depicts mosaic expression of transgene in Z-MYC prostate. Arrows indicate LacZ-positive cells. The frequency of transgene-expressing cells varied depending on glands and lobes, but quantitative analysis indicated that overall, LacZ-positive cells comprised ∼17% of the epithelial cells in any LacZ-positive gland (a) and (b). (c) shows schematic representation of Cre excision of the Z-MYC construct. c-MYC expression is activated and regulated by CMV/Actin promoter after Cre-excision. (B) Immunostaining verifies sporadic c-MYC expression in PbCre4;Z-MYC prostate epithelium of intact mouse (a) and 17 weeks after castration (b). (C) c-MYC colocalizes with cytokeratin 8 (CK8) (a) but not with p63 (b) in PbCre4;Z-MYC mouse prostates.
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pgen-1000542-g001: c-MYC expression in PbCre4;Z-MYC mouse prostate is mosaic and uncoupled from androgen regulation.(A) LacZ stain depicts mosaic expression of transgene in Z-MYC prostate. Arrows indicate LacZ-positive cells. The frequency of transgene-expressing cells varied depending on glands and lobes, but quantitative analysis indicated that overall, LacZ-positive cells comprised ∼17% of the epithelial cells in any LacZ-positive gland (a) and (b). (c) shows schematic representation of Cre excision of the Z-MYC construct. c-MYC expression is activated and regulated by CMV/Actin promoter after Cre-excision. (B) Immunostaining verifies sporadic c-MYC expression in PbCre4;Z-MYC prostate epithelium of intact mouse (a) and 17 weeks after castration (b). (C) c-MYC colocalizes with cytokeratin 8 (CK8) (a) but not with p63 (b) in PbCre4;Z-MYC mouse prostates.

Mentions: To target focal c-MYC expression in the prostate epithelium, we used Z-MYC mice that carry a single copy transgene in which the CMV enhancer/beta actin promoter drives expression of the beta-geo gene and a latent c-MYC transgene [24] (Figure 1A). Staining for beta-galactosidase confirmed mosaic expression in the prostate epithelium (Figure 1A). To induce c-MYC expression focally in the prostate, we crossed Z-MYC mice to PbCre4 mice [25] which express Cre recombinase in the prostatic epithelium (Figure 1A). Bigenic PbCre4;Z-MYC mice expressed c-MYC focally in cytokeratin 8 (CK8) positive prostate luminal epithelial cells but not p63+ basal cells (Figure 1C). Furthermore, c-MYC expression is not abrogated in castrated animals indicating that the use of the CMV enhancer/beta actin promoter in our model has uncoupled prostate-specific expression from androgen-dependent gene regulation (Figure 1B).


Interactions between cells with distinct mutations in c-MYC and Pten in prostate cancer.

Kim J, Eltoum IE, Roh M, Wang J, Abdulkadir SA - PLoS Genet. (2009)

c-MYC expression in PbCre4;Z-MYC mouse prostate is mosaic and uncoupled from androgen regulation.(A) LacZ stain depicts mosaic expression of transgene in Z-MYC prostate. Arrows indicate LacZ-positive cells. The frequency of transgene-expressing cells varied depending on glands and lobes, but quantitative analysis indicated that overall, LacZ-positive cells comprised ∼17% of the epithelial cells in any LacZ-positive gland (a) and (b). (c) shows schematic representation of Cre excision of the Z-MYC construct. c-MYC expression is activated and regulated by CMV/Actin promoter after Cre-excision. (B) Immunostaining verifies sporadic c-MYC expression in PbCre4;Z-MYC prostate epithelium of intact mouse (a) and 17 weeks after castration (b). (C) c-MYC colocalizes with cytokeratin 8 (CK8) (a) but not with p63 (b) in PbCre4;Z-MYC mouse prostates.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2697385&req=5

pgen-1000542-g001: c-MYC expression in PbCre4;Z-MYC mouse prostate is mosaic and uncoupled from androgen regulation.(A) LacZ stain depicts mosaic expression of transgene in Z-MYC prostate. Arrows indicate LacZ-positive cells. The frequency of transgene-expressing cells varied depending on glands and lobes, but quantitative analysis indicated that overall, LacZ-positive cells comprised ∼17% of the epithelial cells in any LacZ-positive gland (a) and (b). (c) shows schematic representation of Cre excision of the Z-MYC construct. c-MYC expression is activated and regulated by CMV/Actin promoter after Cre-excision. (B) Immunostaining verifies sporadic c-MYC expression in PbCre4;Z-MYC prostate epithelium of intact mouse (a) and 17 weeks after castration (b). (C) c-MYC colocalizes with cytokeratin 8 (CK8) (a) but not with p63 (b) in PbCre4;Z-MYC mouse prostates.
Mentions: To target focal c-MYC expression in the prostate epithelium, we used Z-MYC mice that carry a single copy transgene in which the CMV enhancer/beta actin promoter drives expression of the beta-geo gene and a latent c-MYC transgene [24] (Figure 1A). Staining for beta-galactosidase confirmed mosaic expression in the prostate epithelium (Figure 1A). To induce c-MYC expression focally in the prostate, we crossed Z-MYC mice to PbCre4 mice [25] which express Cre recombinase in the prostatic epithelium (Figure 1A). Bigenic PbCre4;Z-MYC mice expressed c-MYC focally in cytokeratin 8 (CK8) positive prostate luminal epithelial cells but not p63+ basal cells (Figure 1C). Furthermore, c-MYC expression is not abrogated in castrated animals indicating that the use of the CMV enhancer/beta actin promoter in our model has uncoupled prostate-specific expression from androgen-dependent gene regulation (Figure 1B).

Bottom Line: These lesions were in all cases associated with loss of Pten protein expression from the wild type allele.We conclude that c-MYC overexpression and Pten deficiency cooperate to promote prostate tumorigenesis, but a p53-dependent apoptotic response may present a barrier to further progression.Our results highlight the utility of inducing mutations focally to model the competitive interactions between cell populations with distinct genetic alterations during tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA.

ABSTRACT
In human somatic tumorigenesis, mutations are thought to arise sporadically in individual cells surrounded by unaffected cells. This contrasts with most current transgenic models where mutations are induced synchronously in entire cell populations. Here we have modeled sporadic oncogene activation using a transgenic mouse in which c-MYC is focally activated in prostate luminal epithelial cells. Focal c-MYC expression resulted in mild pathology, but prostate-specific deletion of a single allele of the Pten tumor suppressor gene cooperated with c-MYC to induce high grade prostatic intraepithelial neoplasia (HGPIN)/cancer lesions. These lesions were in all cases associated with loss of Pten protein expression from the wild type allele. In the prostates of mice with concurrent homozygous deletion of Pten and focal c-MYC activation, double mutant (i.e. c-MYC+;Pten-) cells were of higher grade and proliferated faster than single mutant (Pten-) cells within the same glands. Consequently, double mutant cells outcompeted single mutant cells despite the presence of increased rates of apoptosis in the former. The p53 pathway was activated in Pten-deficient prostate cells and tissues, but c-MYC expression shifted the p53 response from senescence to apoptosis by repressing the p53 target gene p21(Cip1). We conclude that c-MYC overexpression and Pten deficiency cooperate to promote prostate tumorigenesis, but a p53-dependent apoptotic response may present a barrier to further progression. Our results highlight the utility of inducing mutations focally to model the competitive interactions between cell populations with distinct genetic alterations during tumorigenesis.

Show MeSH
Related in: MedlinePlus