Activation of β‐Catenin in mouse prostate causes HGPIN and continuous prostate growth after castration

Yu, Xiuping; Wang, Yongqing; Jiang, Ming; Bierie, Brian; Roy-Burman, Pradip; Shen, Michael M.; Taketo, Makoto Mark; Wills, Marcia L.; Matusik, Robert J.

doi:10.1002/pros.20877

Cited by 108 publications

(114 citation statements)

References 39 publications

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“…One possible signaling pathway that either regulates FOXA2 or is regulated by FOXA2 is the WNT signaling pathway, because mouse models in which Wnt7a, Wnt5a, and Ctnnb1 are ablated all lack uterine glands [21][22][23]39]. Indeed, FOXA2 has been shown to regulate the expression of multiple Wnts, including Wnt3a, Wnt8a, and Wnt7b [44][45][46], and a reciprocal interaction between FOXA2 and WNT signaling has been noted in that CTNNB1, a downstream effector of canonical WNT signaling, can promote Foxa2 [47]. WNT7A signals through the Wnt7a REGULATES NEONATAL UTERINE GLAND MORPHOGENESIS 393 canonical WNT/catenin, beta 1 signaling pathway in other cells and organs [28][29][30][31].…”

Section: Discussionmentioning

confidence: 99%

Postnatal Deletion of Wnt7a Inhibits Uterine Gland Morphogenesis and Compromises Adult Fertility in Mice.

Dunlap¹,

Filant²,

Hayashi³

et al. 2011

Biology of Reproduction

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The success of postnatal uterine morphogenesis dictates, in part, the embryotrophic potential and functional capacity of the adult uterus. The definitive role of Wnt7a in postnatal uterine development and adult function requires a conditional knockout, because global deletion disrupts mü llerian duct patterning, specification, and cell fate in the fetus. The Wnt7a-null uterus appears to be posteriorized because of developmental defects in the embryo, as evidenced by the stratified luminal epithelium that is normally found in the vagina and the presence of short and uncoiled oviducts. To understand the biological role of WNT7A after birth and allow tissue-selective deletion of Wnt7a, we generated loxP-flanked exon 2 mice and conditionally deleted Wnt7a after birth in the uterus by crossing them with Pgr Cre mice. Morphological examination revealed no obvious differences in the vagina, cervix, oviduct, or ovary. The uteri of Wnt7a mutant mice contained no endometrial glands, whereas all other uterine cell types appeared to be normal. Postnatal differentiation of endometrial glands was observed in control mice, but not in mutant mice, between Postnatal Days 3 and 12. Expression of morphoregulatory genes, particularly Foxa2, Hoxa10, Hoxa11, Msx1, and Wnt16, was disrupted in the Wnt7a mutant uteri. Conditional Wnt7a mutant mice were not fertile. Although embryos were present in uteri of mutant mice on Day 3.5 of pregnancy, blastocyst implantation was not observed on Day 5.5. Furthermore, expression of several genes (Foxa2, Lif, Msx1, and Wnt16) was reduced or absent in adult Wnt7a-deleted uteri on Day 3.5 postmating. These results indicate that WNT7A plays a critical role in postnatal uterine gland morphogenesis and function, which are important for blastocyst implantation and fertility in the adult uterus.developmental biology, female reproductive tract, pregnancy, transgenic/knockout model, uterus

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Section: Discussionmentioning

confidence: 99%

Postnatal Deletion of Wnt7a Inhibits Uterine Gland Morphogenesis and Compromises Adult Fertility in Mice.

Dunlap¹,

Filant²,

Hayashi³

et al. 2011

Biology of Reproduction

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“…[7][8][9][10] Studies suggest that cancer cells undergo an epithelialmesenchymal-transition (EMT) program at the initiation of invasion, which is a critical process for metastasis. 11,12 Hallmarks of EMT include loss or decreased protein expression of e-cadherin, increased vimentin and deregulation of b-catenin. These changes in cell morphology are associated with several human cancers and may result in metastasis.…”

Section: Introductionmentioning

confidence: 99%

Obesity-related systemic factors promote an invasive phenotype in prostate cancer cells

Price

Cavazos

Angel

et al. 2012

Prostate Cancer Prostatic Dis

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BACKGROUND: Obesity is associated with larger tumors, shorter time to PSA failure, and higher Gleason scores. However, the mechanism(s) by which obesity promotes aggressive prostate cancer remains unknown. We hypothesize that circulating factors related to obesity promote prostate cancer progression by modulating components of the metastatic cascade.METHODS: Male C57BL/6 mice (6 weeks) were fed an ad libitum diet-induced obesity (60% fat) or control diet (10% fat) for 12 weeks. Serum was collected, metabolic and inflammatory proteins were measured by an antibody array. Sera were used to measure, in vitro, characteristics of a metastatic phenotype. RESULTS:Comparable to obese men, obese sera contained higher levels or leptin, vascular endothelial growth factor, PAI-1, interleukin-6 (IL-6) and lower levels of testosterone. In prostate cells, serum was used to assess: proliferation, invasion, migration, epithelial-mesenchymal-transition (EMT) and matrix metalloproteinase (MMP) activity. LNCaP and PacMetUT1 cells exposed to obese sera increased proliferation, whereas PrEC and DU145 were unaffected. LNCaP, PacMetUT1 and DU145 cancer cells exposed to obese sera resulted in increased invasion, migration and MMP-9 activity. Prostate cancer cells exposed to obese sera showed increased vimentin, dispersion of e-cadherin and b-catenin from the plasma membrane. CONCLUSION:We report, prostate cancer cells exposed to sera from obese mice increases proliferation, invasion, migration, MMP activity and induces changes in proteins critical for EMT.

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“…In transgenic mouse models, conditionally deleted exon3 of β-catenin resulted in production of high-grade PIN (HG-PIN) and induction of Foxa2 re-expression in the adult mouse prostate through Wnt/β-catenin signaling as well as promoting prostate growth even under the conditions of androgen deprivation [125]. In mouse models with the SV40 large T-antigen, which inactivates p53 and Rb [126], or in mice expressing mutated K-ras and form invasive carcinoma [127], or in mice with loss of PTEN expression [128], β-catenin overexpression can promote highly invasive prostate cancer and squamous metaplasia, even in the absence of androgens.…”

Section: Wnt Signaling In Disease Models Of Crpcmentioning

confidence: 99%

Coregulation of srGAP1 by Wnt and Androgen Receptor Signaling: A New Target for Treatment of CRPC

Yokoyama¹

2014

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information , 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBERUNIVERSITY OF CALIFORNIA, Irvine IRVINE CA 92617-3067 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTAndrogen receptor (AR) and Wnt signaling both play a critical role during prostate cancer progression to castration-resistance prostate cancer (CRPC). Over expression of AR can activate transcriptional activities of Wnt signaling pathway and promote CRPC. Recent data in our laboratory showed a potential co-regulation of srGAP1 (Slit-Robo-GTPase activating protein1) and active Wnt and AR signaling in CRPC. srGAP1 is a downstream component of Slit-Robo signaling. Our data showed that srGAP1 is overexpressed in CRPC cell lines (androgen-insensitive prostate cancer) while absent in both androgen-sensitive cells and in normal prostate epithelial cells. We also detected increased srGAP1 and LEF-1 expression in human CRPC tissues compared with normal epithelial prostate and androgen sensitive prostate cancer tissues by immunohistochemistry analysis. When androgen-sensitive LNCaP cells were grown under androgen deprived condition, we observed induced expression of srGAP1. Interestingly, srGAP1 expression was also increased when LNCaP cells were grown under Wnt stimulated conditions. And, srGAP1 expression was decreased when Wnt signaling was inhibited by a Wnt antagonist Wntinhibitory factor-1 (WIF-1) in CRPC cell lines. Chromatin immmunoprecipitation assay was performed to examine whether Wnt transcription factor TCF-4 binds to the srGAP1 promoter. Overexpression of WIF-1 inhibited the promoter activity of srGAP1. Taken together, our results indicated that srGAP1 is co-regulated by both Wnt and AR signaling and srGAP1 may be a new potential Wnt target gene in castrationresistance prostate cancer. SUBJECT TERMS INTRODUCTION:Prostate cancer is one of the most common cancer diagnosed in t...

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Activation of β‐Catenin in mouse prostate causes HGPIN and continuous prostate growth after castration

Cited by 108 publications

References 39 publications

Postnatal Deletion of Wnt7a Inhibits Uterine Gland Morphogenesis and Compromises Adult Fertility in Mice.

Postnatal Deletion of Wnt7a Inhibits Uterine Gland Morphogenesis and Compromises Adult Fertility in Mice.

Obesity-related systemic factors promote an invasive phenotype in prostate cancer cells

Coregulation of srGAP1 by Wnt and Androgen Receptor Signaling: A New Target for Treatment of CRPC

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