Genetically Engineered Mouse Models of Prostate Cancer in the Postgenomic Era

Abate‐Shen, Cory

doi:10.1101/cshperspect.a030528

Cited by 50 publications

(33 citation statements)

References 168 publications

(229 reference statements)

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“…Bone is the predominant site of metastasis in this disease, although a subset of highly aggressive PCa disseminates to the lung and soft tissues (Arriaga and Abate-Shen, 2019). The biology of lethal metastatic PCa is poorly understood, and there are few murine models to date that recapitulate this pattern of aggressiveness (Arriaga and Abate-Shen, 2019). Our study provides the field with an invaluable model to study the process of PCa dissemination in an immune-competent and tissue-specific context.…”

Section: Resultsmentioning

confidence: 99%

Genetic manipulation of LKB1 elicits lethal metastatic prostate cancer

Heřmanová

Zúñiga-García

Caro‐Maldonado

et al. 2020

Journal of Experimental Medicine

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Gene dosage is a key defining factor to understand cancer pathogenesis and progression, which requires the development of experimental models that aid better deconstruction of the disease. Here, we model an aggressive form of prostate cancer and show the unconventional association of LKB1 dosage to prostate tumorigenesis. Whereas loss of Lkb1 alone in the murine prostate epithelium was inconsequential for tumorigenesis, its combination with an oncogenic insult, illustrated by Pten heterozygosity, elicited lethal metastatic prostate cancer. Despite the low frequency of LKB1 deletion in patients, this event was significantly enriched in lung metastasis. Modeling the role of LKB1 in cellular systems revealed that the residual activity retained in a reported kinase-dead form, LKB1K78I, was sufficient to hamper tumor aggressiveness and metastatic dissemination. Our data suggest that prostate cells can function normally with low activity of LKB1, whereas its complete absence influences prostate cancer pathogenesis and dissemination.

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Section: Resultsmentioning

confidence: 99%

Genetic manipulation of LKB1 elicits lethal metastatic prostate cancer

Heřmanová

Zúñiga-García

Caro‐Maldonado

et al. 2020

Journal of Experimental Medicine

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“…In almost half of patients with prostate cancer, the tumor carries one of recurrent translocations that place one of the genes from the ETS family (ERG, ETV1, ETV4, ETV5, FLI1) downstream to the promoter of a gene active in the prostate, with consequent aberrant overexpression of the respective ETS gene [2][3][4][5]. The role of the ETS genes in prostate carcinogenesis has been investigated in transgenic mice models with a prostate-specific ETS overexpression [6,7]. The results have not been always concordant: some studies suggest that ERG or ETV1 overexpression promotes premalignant in situ lesions (equivalent to prostatic intraepithelial neoplasia, PIN) [8][9][10][11][12], whereas other studies suggest that this overexpression is not sufficient to cause the onset of cancer [13][14][15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

ETV4 promotes late development of prostatic intraepithelial neoplasia and cell proliferation through direct and p53-mediated downregulation of p21

et al. 2020

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Background: ETV4 is one of the ETS proteins overexpressed in prostate cancer (PC) as a result of recurrent chromosomal translocations. In human prostate cell lines, ETV4 promotes migration, invasion, and proliferation; however, its role in PC has been unclear. In this study, we have explored the effects of ETV4 expression in the prostate in a novel transgenic mouse model. Methods: We have created a mouse model with prostate-specific expression of ETV4 (ETV4 mice). By histochemical and molecular analysis, we have investigated in these engineered mice the expression of p21, p27, and p53. The implications of our in vivo findings have been further investigated in human cells lines by chromatin-immunoprecipitation (ChIP) and luciferase assays. Results: ETV4 mice, from two independent transgenic lines, have increased cell proliferation in their prostate and two-thirds of them, by the age of 10 months, developed mouse prostatic intraepithelial neoplasia (mPIN). In these mice, cdkn1a and its p21 protein product were reduced compared to controls; p27 protein was also reduced. By ChIP assay in human prostate cell lines, we show that ETV4 binds to a specific site (-704/-696 bp upstream of the transcription start) in the CDKN1A promoter that was proven, by luciferase assay, to be functionally competent. ETV4 further controls CDKN1A expression by downregulating p53 protein: this reduction of p53 was confirmed in vivo in ETV4 mice. Conclusions: ETV4 overexpression results in the development of mPIN but not in progression to cancer. ETV4 increases prostate cell proliferation through multiple mechanisms, including downregulation of CDKN1A and its p21 protein product: this in turn is mediated through direct binding of ETV4 to the CDKN1A promoter and through the ETV4-mediated decrease of p53. This multi-faceted role of ETV4 in prostate cancer makes it a potential target for novel therapeutic approaches that could be explored in this ETV4 transgenic model.

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“…Multiple lines of evidence in the literature have indicated that PTEN plays a haploinsufficient tumor-suppressive role. Transgenic mouse models have shown that PTEN haploinsufficiency or heterozygosity in mouse prostate epithelium can cause prostate lesions, whereas homozygous PTEN deletion causes prostate carcinoma [ 20 , 23 , 94 ]. Moreover, PTEN loss has been shown to cooperate with other oncogenic events to accelerate prostate cancer progression in vivo in a dose-dependent manner, and heterozygous loss of PTEN has been shown to accelerate prostate cancer progression in some clinical datasets [ 22 , 76 , 79 , 95 , 96 , 97 ].…”

Section: Targeting Pten-deficient Prostate Cancermentioning

confidence: 99%

The PTEN Conundrum: How to Target PTEN-Deficient Prostate Cancer

Turnham

Bullock

Dass

et al. 2020

Cells

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Loss of the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN), which negatively regulates the PI3K–AKT–mTOR pathway, is strongly linked to advanced prostate cancer progression and poor clinical outcome. Accordingly, several therapeutic approaches are currently being explored to combat PTEN-deficient tumors. These include classical inhibition of the PI3K–AKT–mTOR signaling network, as well as new approaches that restore PTEN function, or target PTEN regulation of chromosome stability, DNA damage repair and the tumor microenvironment. While targeting PTEN-deficient prostate cancer remains a clinical challenge, new advances in the field of precision medicine indicate that PTEN loss provides a valuable biomarker to stratify prostate cancer patients for treatments, which may improve overall outcome. Here, we discuss the clinical implications of PTEN loss in the management of prostate cancer and review recent therapeutic advances in targeting PTEN-deficient prostate cancer. Deepening our understanding of how PTEN loss contributes to prostate cancer growth and therapeutic resistance will inform the design of future clinical studies and precision-medicine strategies that will ultimately improve patient care.

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Genetically Engineered Mouse Models of Prostate Cancer in the Postgenomic Era

Cited by 50 publications

References 168 publications

Genetic manipulation of LKB1 elicits lethal metastatic prostate cancer

Genetic manipulation of LKB1 elicits lethal metastatic prostate cancer

ETV4 promotes late development of prostatic intraepithelial neoplasia and cell proliferation through direct and p53-mediated downregulation of p21

The PTEN Conundrum: How to Target PTEN-Deficient Prostate Cancer

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