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Molecular Cancer
Published in: Molecular Cancer 1/2018

Open Access 01-12-2018 | Research

AR–PDEF pathway promotes tumour proliferation and upregulates MYC-mediated gene transcription by promoting MAD1 degradation in ER-negative breast cancer

Authors: Lu Cao, Cong Xu, Guomin Xiang, Fang Liu, Xiaozhen Liu, Congying Li, Jing Liu, Qingxiang Meng, Jiao Jiao, Yun Niu

Published in: Molecular Cancer | Issue 1/2018

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Abstract

Background

Androgen receptor (AR) is expressed in 60%~ 70% oestrogen receptor (ER)-negative breast cancer (BC) cases and promotes the growth of this cancer subtype. Expression of prostate-derived Ets factor (PDEF), a transcription factor, is highly restricted to epithelial cells in hormone-regulated tissues. MYC and its negative regulator MAD1 play an important role in BC progression. Previously, we found that PDEF expression is strongly correlated with AR expression. However, the relationship between AR and PDEF and the function of PDEF in ER-negative BC proliferation are unclear.

Methods

AR and PDEF expression in ER-negative BC tissues and cell lines was determined by performing immunohistochemistry or western blotting. Protein expression levels and location were analysed by performing western blotting, RT-qPCR and immunofluorescence staining. Co-immunoprecipitation and chromatin immunoprecipitation assays were performed to validate the regulation of AR–PDEF–MAD1–MYC axis. Moreover, the effect of AR and PDEF on BC progression was investigated both in vitro and in vivo.

Results

We found that PDEF was overexpressed in ER-negative BC tissues and cell lines and appeared to function as an oncogene. PDEF expression levels were strongly correlated with AR expression in ER-negative BC, and PDEF transcription was positively regulated by AR. PDEF upregulated MYC-mediated gene transcription by promoting MAD1 degradation in ER-negative BC. Finally, we found that compared with the inhibition of AR expression alone, simultaneous inhibition of AR and PDEF expression further suppressed tumour proliferation both in vitro and in vivo.

Conclusions

Our data highlight the role of the AR–PDEF–MAD1–MYC axis in BC progression and suggest that PDEF can be used as a new clinical therapeutic target for treating ER-negative BC.
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Literature
1.
2.
3.
Farmer P, Bonnefoi H, Becette V, Tubiana-Hulin M, Fumoleau P, Larsimont D, Macgrogan G, Bergh J, Cameron D, Goldstein D, et al. Identification of molecular apocrine breast tumours by microarray analysis. Oncogene. 2005;24:4660–71.CrossRefPubMed
4.
Pietri E, Conteduca V, Andreis D, Massa I, Melegari E, Sarti S, Cecconetto L, Schirone A, Bravaccini S, Serra P, et al. Androgen receptor signaling pathways as a target for breast cancer treatment. Endocr Relat Cancer. 2016;23:R485–98.CrossRefPubMed
5.
Mahajan N. Signatures of prostate-derived Ets factor (PDEF) in cancer. Tumour Biol. 2016;37(11):14335–340.CrossRefPubMed
6.
Ghadersohi A, Sood AK. Prostate epithelium-derived Ets transcription factor mRNA is overexpressed in human breast tumors and is a candidate breast tumor marker and a breast tumor antigen. Clin Cancer Res. 2001;7:2731–8.PubMed
7.
Oettgen P, Finger E, Sun Z, Akbarali Y, Thamrongsak U, Boltax J, Grall F, Dube A, Weiss A, Brown L, et al. PDEF, a novel prostate epithelium-specific ets transcription factor, interacts with the androgen receptor and activates prostate-specific antigen gene expression. J Biol Chem. 2000;275:1216–25.CrossRefPubMed
8.
Gunawardane RN, Sgroi DC, Wrobel CN, Koh E, Daley GQ, Brugge JS. Novel role for PDEF in epithelial cell migration and invasion. Cancer Res. 2005;65:11572–80.CrossRefPubMedCentralPubMed
9.
Feldman RJ, Sementchenko VI, Gayed M, Fraig MM, Watson DK. Pdef expression in human breast cancer is correlated with invasive potential and altered gene expression. Cancer Res. 2003;63:4626–31.PubMed
10.
Gu X, Zerbini LF, Otu HH, Bhasin M, Yang Q, Joseph MG, Grall F, Onatunde T, Correa RG, Libermann TA. Reduced PDEF expression increases invasion and expression of mesenchymal genes in prostate cancer cells. Cancer Res. 2007;67:4219–26.CrossRefPubMed
11.
Moussa O, Turner DP, Feldman RJ, Sementchenko VI, McCarragher BD, Desouki MM, Fraig M, Watson DK. PDEF is a negative regulator of colon cancer cell growth and migration. J Cell Biochem. 2009;108:1389–98.CrossRefPubMedCentralPubMed
12.
Turner DP, Moussa O, Sauane M, Fisher PB, Watson DK. Prostate-derived ETS factor is a mediator of metastatic potential through the inhibition of migration and invasion in breast cancer. Cancer Res. 2007;67:1618–25.CrossRefPubMed
13.
Buchwalter G, Hickey MM, Cromer A, Selfors LM, Gunawardane RN, Frishman J, Jeselsohn R, Lim E, Chi D, Fu X, et al. PDEF promotes luminal differentiation and acts as a survival factor for ER-positive breast cancer cells. Cancer Cell. 2013;23:753–67.CrossRefPubMedCentralPubMed
14.
Doane AS, Danso M, Lal P, Donaton M, Zhang L, Hudis C, Gerald WL. An estrogen receptor-negative breast cancer subset characterized by a hormonally regulated transcriptional program and response to androgen. Oncogene. 2006;25:3994–4008.CrossRefPubMed
15.
16.
Todorovic-Rakovic N, Neskovic-Konstantinovic Z, Nikolic-Vukosavljevic D. C-myc as a predictive marker for chemotherapy in metastatic breast cancer. Clin Exp Med. 2012;12:217–23.CrossRefPubMed
17.
Qu J, Zhao X, Wang J, Liu X, Yan Y, Liu L, Cai H, Qu H, Lu N, Sun Y, et al. MYC overexpression with its prognostic and clinicopathological significance in breast cancer. Oncotarget. 2017;8:93998–4008.PubMedPubMedCentral
18.
19.
Gupta N, Jung K, Wu C, Alshareef A, Alqahtani H, Damaraju S, Mackey JR, Ghosh S, Sabri S, Abdulkarim BS, et al. High Myc expression and transcription activity underlies intra-tumoral heterogeneity in triple-negative breast cancer. Oncotarget. 2017;8:28101–15.PubMedPubMedCentral
20.
21.
Cao L, Qi L, Zhang L, Song W, Yu Y, Xu C, Li L, Guo Y, Yang L, Liu C, et al. Human nonsense-mediated RNA decay regulates EMT by targeting the TGF-ss signaling pathway in lung adenocarcinoma. Cancer Lett. 2017;403:246–59.CrossRefPubMed
22.
Workman P, Aboagye EO, Balkwill F, Balmain A, Bruder G, Chaplin DJ, Double JA, Everitt J, Farningham DA, Glennie MJ, et al. Guidelines for the welfare and use of animals in cancer research. Br J Cancer. 2010;102:1555–77.CrossRefPubMedCentralPubMed
23.
Robinson JL, Macarthur S, Ross-Innes CS, Tilley WD, Neal DE, Mills IG, Carroll JS. Androgen receptor driven transcription in molecular apocrine breast cancer is mediated by FoxA1. EMBO J. 2011;30:3019–27.CrossRefPubMedCentralPubMed
24.
Subik K, Lee JF, Baxter L, Strzepek T, Costello D, Crowley P, Xing L, Hung MC, Bonfiglio T, Hicks DG, Tang P. The expression patterns of ER, PR, HER2, CK5/6, EGFR, Ki-67 and AR by Immunohistochemical analysis in breast Cancer cell lines. Breast Cancer (Auckl). 2010;4:35–41.PubMedCentral
25.
Proverbs-Singh T, Feldman JL, Morris MJ, Autio KA, Traina TA. Targeting the androgen receptor in prostate and breast cancer: several new agents in development. Endocr Relat Cancer. 2015;22:R87–R106.CrossRefPubMedCentralPubMed
26.
Huang L, Johnson KA, Mariotto AB, Dignam JJ, Feuer EJ. Population-based survival-cure analysis of ER-negative breast cancer. Breast Cancer Res Treat. 2010;123:257–64.CrossRefPubMed
27.
Garcia-Closas M, Couch FJ, Lindstrom S, Michailidou K, Schmidt MK, Brook MN, Orr N, Rhie SK, Riboli E, Feigelson HS, et al. Genome-wide association studies identify four ER negative-specific breast cancer risk loci. Nat Genet. 2013;45:392–8. 398e391-392CrossRefPubMedCentralPubMed
28.
Kono M, Fujii T, Lim B, Karuturi MS, Tripathy D, Ueno NT. Androgen receptor function and androgen receptor-targeted therapies in breast Cancer: a review. JAMA Oncol. 2017;3:1266–73.CrossRefPubMed
29.
Kim JY, Park K, Lee E, Jung HH, Ahn JS, Im YH, Park WY, Park YH. The effect of androgen receptor expression on clinical characterization of metastatic breast cancer. Oncotarget. 2017;8:8693–706.PubMedPubMedCentral
30.
Liu CY, Wu CY, Petrossian K, Huang TT, Tseng LM, Chen S. Treatment for the endocrine resistant breast cancer: current options and future perspectives. J Steroid Biochem Mol Biol. 2017;172:166–75.CrossRefPubMed
31.
Yu Q, Niu Y, Liu N, Zhang JZ, Liu TJ, Zhang RJ, Wang SL, Ding XM, Xiao XQ. Expression of androgen receptor in breast cancer and its significance as a prognostic factor. Ann Oncol. 2011;22:1288–94.CrossRefPubMed
32.
Rodabaugh KJ, Mhawech-Fauceglia P, Groth J, Lele S, Sood AK. Prostate-derived Ets factor is overexpressed in serous epithelial ovarian tumors. Int J Gynecol Pathol. 2007;26:10–5.CrossRefPubMed
33.
Chen EB, Zhou SL, Pang XG, Yin D, Miao PZ, Yang Y, Chen Q, Zhu K, Gao DM, Liu TS, et al. Prostate-derived ETS factor improves prognosis and represses proliferation and invasion in hepatocellular carcinoma. Oncotarget. 2017;8:52488–500.PubMedPubMedCentral
34.
Noah TK, Lo YH, Price A, Chen G, King E, Washington MK, Aronow BJ, Shroyer NF. SPDEF functions as a colorectal tumor suppressor by inhibiting beta-catenin activity. Gastroenterology. 2013;144:1012–23. e1016CrossRefPubMed
35.
McArthur GA, Foley KP, Fero ML, Walkley CR, Deans AJ, Roberts JM, Eisenman RN. MAD1 and p27(KIP1) cooperate to promote terminal differentiation of granulocytes and to inhibit Myc expression and cyclin E-CDK2 activity. Mol Cell Biol. 2002;22:3014–23.CrossRefPubMedCentralPubMed
36.
Hu J, Banerjee A, Goss DJ. Assembly of b/HLH/z proteins c-Myc, max, and Mad1 with cognate DNA: importance of protein-protein and protein-DNA interactions. Biochemistry. 2005;44:11855–63.CrossRefPubMed
37.
Poortinga G, Hannan KM, Snelling H, Walkley CR, Jenkins A, Sharkey K, Wall M, Brandenburger Y, Palatsides M, Pearson RB, et al. MAD1 and c-MYC regulate UBF and rDNA transcription during granulocyte differentiation. EMBO J. 2004;23:3325–35.CrossRefPubMedCentralPubMed
38.
Nahleh Z. Androgen receptor as a target for the treatment of hormone receptor-negative breast cancer: an unchartered territory. Future Oncol. 2008;4:15–21.CrossRefPubMed
39.
Lundin KB, Henningson M, Hietala M, Ingvar C, Rose C, Jernstrom H. Androgen receptor genotypes predict response to endocrine treatment in breast cancer patients. Br J Cancer. 2011;105:1676–83.CrossRefPubMedCentralPubMed
40.
Anestis A, Karamouzis MV, Dalagiorgou G, Papavassiliou AG. Is androgen receptor targeting an emerging treatment strategy for triple negative breast cancer? Cancer Treat Rev. 2015;41:547–53.CrossRefPubMed
41.
Traina TA, Miller K, Yardley DA, Eakle J, Schwartzberg LS, O'Shaughnessy J, Gradishar W, Schmid P, Winer E, Kelly C, et al. Enzalutamide for the treatment of androgen receptor-expressing triple-negative breast Cancer. J Clin Oncol. 2018;36:884–90.CrossRefPubMedCentralPubMed
42.
Gucalp A, Tolaney S, Isakoff SJ, Ingle JN, Liu MC, Carey LA, Blackwell K, Rugo H, Nabell L, Forero A, et al. Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic breast Cancer. Clin Cancer Res. 2013;19:5505–12.CrossRefPubMedCentralPubMed
Metadata
Title
AR–PDEF pathway promotes tumour proliferation and upregulates MYC-mediated gene transcription by promoting MAD1 degradation in ER-negative breast cancer
Authors
Lu Cao
Cong Xu
Guomin Xiang
Fang Liu
Xiaozhen Liu
Congying Li
Jing Liu
Qingxiang Meng
Jiao Jiao
Yun Niu
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2018
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-018-0883-0

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