Deletion of Tumor Suppressors Adenomatous Polyposis Coli and Smad4 in Murine Luminal Epithelial Cells Causes Invasive Prostate Cancer and Loss of Androgen Receptor Expression

Overview

Journal Oncotarget

Specialty Oncology

Date 2017 Nov 9

PMID 29113300

Citations 5

Authors

Kenneth C Valkenburg

Angelo M De Marzo

Bart O Williams

Affiliations

Soon will be listed here.

Abstract

Prostate cancer is the most diagnosed non-skin cancer in the US and kills approximately 27,000 men per year in the US. Additional genetic mouse models are needed that recapitulate the heterogeneous nature of human prostate cancer. The Wnt/beta-catenin signaling pathway is important for human prostate tumorigenesis and metastasis, and also drives tumorigenesis in mouse models. Loss of Smad4 has also been found in human prostate cancer and drives tumorigenesis and metastasis when coupled with other genetic aberrations in mouse models. In this work, we concurrently deleted Smad4 and the tumor suppressor and endogenous Wnt/beta-catenin inhibitor adenomatous polyposis coli (Apc) in luminal prostate cells in mice. This double conditional knockout model produced invasive castration-resistant prostate carcinoma with no evidence of metastasis. We observed mixed differentiation phenotypes, including basaloid and squamous differentiation. Interestingly, tumor cells in this model commonly lose androgen receptor expression. In addition, tumors disappear in these mice during androgen cycling (castration followed by testosterone reintroduction). These mice model non-metastatic castration resistant prostate cancer and should provide novel information for tumors that have genetic aberrations in the Wnt pathway or Smad4.

Citing Articles

Exploring the Wnt Pathway as a Therapeutic Target for Prostate Cancer.

Koushyar S, Meniel V, Phesse T, Pearson H Biomolecules. 2022; 12(2).

PMID: 35204808 PMC: 8869457. DOI: 10.3390/biom12020309.

MicroRNA-539 functions as a tumour suppressor in prostate cancer via the TGF-β/Smad4 signalling pathway by down-regulating DLX1.

Sun B, Fan Y, Yang A, Liang L, Cao J J Cell Mol Med. 2019; 23(9):5934-5948.

PMID: 31298493 PMC: 6714137. DOI: 10.1111/jcmm.14402.

Leveraging the Role of the Metastatic Associated Protein Anterior Gradient Homologue 2 in Unfolded Protein Degradation: A Novel Therapeutic Biomarker for Cancer.

Alsereihi R, Schulten H, Bakhashab S, Saini K, Al-Hejin A, Hussein D Cancers (Basel). 2019; 11(7).

PMID: 31247903 PMC: 6678570. DOI: 10.3390/cancers11070890.

Prostate-specific markers to identify rare prostate cancer cells in liquid biopsies.

van der Toom E, Axelrod H, de la Rosette J, de Reijke T, Pienta K, Valkenburg K Nat Rev Urol. 2018; 16(1):7-22.

PMID: 30479377 PMC: 6324967. DOI: 10.1038/s41585-018-0119-5.

High Expression of KIF22/Kinesin-Like DNA Binding Protein (Kid) as a Poor Prognostic Factor in Prostate Cancer Patients.

Zhang Z, Xie H, Zhu S, Chen X, Yu J, Shen T Med Sci Monit. 2018; 24:8190-8197.

PMID: 30427826 PMC: 6247746. DOI: 10.12659/MSM.912643.

References

Robinson D, Van Allen E, Wu Y, Schultz N, Lonigro R, Mosquera J . Integrative clinical genomics of advanced prostate cancer. Cell. 2015; 161(5):1215-1228. PMC: 4484602. DOI: 10.1016/j.cell.2015.05.001. View

Valkenburg K, Pienta K . Drug discovery in prostate cancer mouse models. Expert Opin Drug Discov. 2015; 10(9):1011-24. PMC: 5889079. DOI: 10.1517/17460441.2015.1052790. View

Wyatt A, Mo F, Wang K, McConeghy B, Brahmbhatt S, Jong L . Heterogeneity in the inter-tumor transcriptome of high risk prostate cancer. Genome Biol. 2014; 15(8):426. PMC: 4169643. DOI: 10.1186/s13059-014-0426-y. View

Montgomery R, Mostaghel E, Vessella R, Hess D, Kalhorn T, Higano C . Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008; 68(11):4447-54. PMC: 2536685. DOI: 10.1158/0008-5472.CAN-08-0249. View

Olama A, Kote-Jarai Z, Berndt S, Conti D, Schumacher F, Han Y . A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer. Nat Genet. 2014; 46(10):1103-9. PMC: 4383163. DOI: 10.1038/ng.3094. View

Aitchison A, Veerakumarasivam A, Vias M, Kumar R, Hamdy F, Neal D . Promoter methylation correlates with reduced Smad4 expression in advanced prostate cancer. Prostate. 2008; 68(6):661-74. DOI: 10.1002/pros.20730. View

Chen G, Shukeir N, Potti A, Sircar K, Aprikian A, Goltzman D . Up-regulation of Wnt-1 and beta-catenin production in patients with advanced metastatic prostate carcinoma: potential pathogenetic and prognostic implications. Cancer. 2004; 101(6):1345-56. DOI: 10.1002/cncr.20518. View

Valkenburg K, Yu X, De Marzo A, Spiering T, Matusik R, Williams B . Activation of Wnt/β-catenin signaling in a subpopulation of murine prostate luminal epithelial cells induces high grade prostate intraepithelial neoplasia. Prostate. 2014; 74(15):1506-20. PMC: 4175140. DOI: 10.1002/pros.22868. View

Ding Z, Wu C, Chu G, Xiao Y, Ho D, Zhang J . SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression. Nature. 2011; 470(7333):269-73. PMC: 3753179. DOI: 10.1038/nature09677. View

10.

Ding Z, Wu C, Jaskelioff M, Ivanova E, Kost-Alimova M, Protopopov A . Telomerase reactivation following telomere dysfunction yields murine prostate tumors with bone metastases. Cell. 2012; 148(5):896-907. PMC: 3629723. DOI: 10.1016/j.cell.2012.01.039. View

11.

Qian C, Knol J, Igarashi P, Lin F, Zylstra U, Teh B . Cystic renal neoplasia following conditional inactivation of apc in mouse renal tubular epithelium. J Biol Chem. 2004; 280(5):3938-45. DOI: 10.1074/jbc.M410697200. View

12.

Wu X, Wu J, Huang J, Powell W, Zhang J, Matusik R . Generation of a prostate epithelial cell-specific Cre transgenic mouse model for tissue-specific gene ablation. Mech Dev. 2001; 101(1-2):61-9. DOI: 10.1016/s0925-4773(00)00551-7. View

13.

Wyatt A, Mo F, Wang Y, Collins C . The diverse heterogeneity of molecular alterations in prostate cancer identified through next-generation sequencing. Asian J Androl. 2013; 15(3):301-8. PMC: 3739651. DOI: 10.1038/aja.2013.13. View

14.

Bruxvoort K, Charbonneau H, Giambernardi T, Goolsby J, Qian C, Zylstra C . Inactivation of Apc in the mouse prostate causes prostate carcinoma. Cancer Res. 2007; 67(6):2490-6. DOI: 10.1158/0008-5472.CAN-06-3028. View

15.

Stanbrough M, Bubley G, Ross K, Golub T, Rubin M, Penning T . Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 2006; 66(5):2815-25. DOI: 10.1158/0008-5472.CAN-05-4000. View

16.

Lee S, Tian J, Huang C, Ma Z, Lai K, Hsiao H . Suppressor role of androgen receptor in proliferation of prostate basal epithelial and progenitor cells. J Endocrinol. 2012; 213(2):173-82. DOI: 10.1530/JOE-11-0474. View

17.

Denmeade S, Isaacs J . Bipolar androgen therapy: the rationale for rapid cycling of supraphysiologic androgen/ablation in men with castration resistant prostate cancer. Prostate. 2010; 70(14):1600-7. PMC: 4124628. DOI: 10.1002/pros.21196. View

18.

Ueno K, Hirata H, Shahryari V, Deng G, Tanaka Y, Tabatabai Z . microRNA-183 is an oncogene targeting Dkk-3 and SMAD4 in prostate cancer. Br J Cancer. 2013; 108(8):1659-67. PMC: 3668476. DOI: 10.1038/bjc.2013.125. View

19.

Nacusi L, Tindall D . Androgen receptor abnormalities in castration-recurrent prostate cancer. Expert Rev Endocrinol Metab. 2010; 4(5):417-422. PMC: 2835169. DOI: 10.1586/eem.09.34. View

20.

Isaacs J, DAntonio J, Chen S, Antony L, Dalrymple S, Ndikuyeze G . Adaptive auto-regulation of androgen receptor provides a paradigm shifting rationale for bipolar androgen therapy (BAT) for castrate resistant human prostate cancer. Prostate. 2012; 72(14):1491-505. PMC: 3374010. DOI: 10.1002/pros.22504. View