The histone methyltransferase EZH2 promotes mammary stem and luminal progenitor cell expansion, metastasis and inhibits estrogen receptor-positive cellular differentiation in a model of basal breast cancer

Wu,Jianchun; Crowe,David L.

doi:10.3892/or.2015.4003

The histone methyltransferase EZH2 promotes mammary stem and luminal progenitor cell expansion, metastasis and inhibits estrogen receptor-positive cellular differentiation in a model of basal breast cancer

Authors:
- Jianchun Wu
- David L. Crowe
View Affiliations

Affiliations: University of Illinois Cancer Center, Chicago, IL 60612, USA
Published online on: May 21, 2015 https://doi.org/10.3892/or.2015.4003
Pages: 455-460

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Mammary stem cells (MSCs) are the progenitor population for human breast epithelia. MSCs give rise during mammary gland development to estrogen receptor (ER)-negative basal cells and the ER- luminal progenitor (LP) population which maintains ER+ and ER- luminal cells. The MSC population is expanded and tumorigenic in some mouse mammary cancer models, and these tumor-initiating cells have been isolated from human breast cancers. MSC expansion is associated with aggressive biological behavior in human breast cancer. The LP population is tumorigenic in some mouse mammary cancer models, and is the progenitor population of basal breast cancer in humans. The enhancer of zeste homolog 2 (EZH2) is a methyltransferase which catalyzes lysine 27 methylation in histone H3 resulting in suppression of target gene expression. The histone demethylase JMJD3 opposes the activity of EZH2 by demethylating histone H3 lysine 27. EZH2 is a member of the polycomb group of proteins which regulates cell type identity. EZH2 expression was found to be increased in histologically normal human breast tissue among women with high breast cancer risk, and was elevated in ductal hyperplasia and ductal carcinoma in situ. EZH2 overexpression is associated with poorly differentiated and aggressive breast cancer in humans. However, the mechanisms by which EZH2 results in increased breast cancer risk and aggressive tumors are not completely characterized. Using in vivo transplantation of mammary cancer stem cells transduced with EZH2 or JMJD3 shRNAs, we demonstrated that EZH2 promotes mammary stem and LP cell expansion, metastasis and inhibits ER-positive cellular differentiation.

View Figures

View References

1	American Cancer Society: Cancer Facts and Figures 2013. American Cancer Society, Inc.; Atlanta: 2013
2	Mariotto AB, Yabroff KR, Shao Y, Feuer EJ and Brown ML: Projections of the cost of cancer care in the United States: 2010–2020. J Natl Cancer Inst. 103:117–128. 2011. View Article : Google Scholar : PubMed/NCBI
3	Crowe DL, Parsa B and Sinha UK: Relationships between stem cells and cancer stem cells. Histol Histopathol. 19:505–509. 2004.PubMed/NCBI
4	Stingl J, Raouf A, Emerman JT and Eaves CJ: Epithelial progenitors in the normal human mammary gland. J Mammary Gland Biol Neoplasia. 10:49–59. 2005. View Article : Google Scholar : PubMed/NCBI
5	Visvader JE: Keeping abreast of the mammary epithelial hierarchy and breast tumorigenesis. Genes Dev. 23:2563–2577. 2009. View Article : Google Scholar : PubMed/NCBI
6	Visvader JE and Lindeman GJ: Mammary stem cells and mammopoiesis. Cancer Res. 66:9798–9801. 2006. View Article : Google Scholar : PubMed/NCBI
7	Van Keymeulen A, Rocha AS, Ousset M, Beck B, Bouvencourt G, Rock J, Sharma N, Dekoninck S and Blanpain C: Distinct stem cells contribute to mammary gland development and maintenance. Nature. 479:189–193. 2011. View Article : Google Scholar : PubMed/NCBI
8	Shehata M, Teschendorff A, Sharp G, Novcic N, Russell IA, Avril S, Prater M, Eirew P, Caldas C and Watson CJ: Phenotypic and functional characterisation of the luminal cell hierarchy of the mammary gland. Breast Cancer Res. 14:R1342012. View Article : Google Scholar : PubMed/NCBI
9	Dontu G, Abdallah WM, Foley JM, Jackson KW, Clarke MF, Kawamura MJ and Wicha MS: In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev. 17:1253–1270. 2003. View Article : Google Scholar : PubMed/NCBI
10	Shackleton M, Vaillant F, Simpson KJ, Stingl J, Smyth GK, Asselin-Labat ML, Wu L, Lindeman GJ and Visvader JE: Generation of a functional mammary gland from a single stem cell. Nature. 439:84–88. 2006. View Article : Google Scholar : PubMed/NCBI
11	Stingl J, Eirew P, Ricketson I, Shackleton M, Vaillant F, Choi D, Li HI and Eaves CJ: Purification and unique properties of mammary epithelial stem cells. Nature. 439:993–997. 2006.PubMed/NCBI
12	Li Y, Welm B, Podsypanina K, Huang S, Chamorro M, Zhang X, Rowlands T, Egeblad M, Cowin P, Werb Z, et al: Evidence that transgenes encoding components of the Wnt signaling pathway preferentially induce mammary cancers from progenitor cells. Proc Natl Acad Sci USA. 100:15853–15858. 2003. View Article : Google Scholar : PubMed/NCBI
13	Liu BY, McDermott SP, Khwaja SS and Alexander CM: The transforming activity of Wnt effectors correlates with their ability to induce the accumulation of mammary progenitor cells. Proc Natl Acad Sci USA. 101:4158–4163. 2004. View Article : Google Scholar : PubMed/NCBI
14	Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ and Clarke MF: Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA. 100:3983–3988. 2003. View Article : Google Scholar : PubMed/NCBI
15	Ponti D, Costa A, Zaffaroni N, Pratesi G, Petrangolini G, Coradini D, Pilotti S, Pierotti MA and Daidone MG: Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res. 65:5506–5511. 2005. View Article : Google Scholar : PubMed/NCBI
16	Charafe-Jauffret E, Ginestier C, Iovino F, Wicinski J, Cervera N, Finetti P, Hur MH, Diebel ME, Monville F, Dutcher J, et al: Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature. Cancer Res. 69:1302–1313. 2009. View Article : Google Scholar : PubMed/NCBI
17	Han JS and Crowe DL: Tumor initiating cancer stem cells from human breast cancer cell lines. Int J Oncol. 34:1449–1453. 2009.PubMed/NCBI
18	Liu H, Patel MR, Prescher JA, Patsialou A, Qian D, Lin J, Wen S, Chang YF, Bachmann MH, Shimono Y, et al: Cancer stem cells from human breast tumors are involved in spontaneous metastases in orthotopic mouse models. Proc Natl Acad Sci USA. 107:18115–18120. 2010. View Article : Google Scholar : PubMed/NCBI
19	Woodward WA, Chen MS, Behbod F, Alfaro MP, Buchholz TA and Rosen JM: WNT/beta-catenin mediates radiation resistance of mouse mammary progenitor cells. Proc Natl Acad Sci USA. 104:618–623. 2007. View Article : Google Scholar : PubMed/NCBI
20	Pece S, Tosoni D, Confalonieri S, Mazzarol G, Vecchi M, Ronzoni S, Bernard L, Viale G, Pelicci PG and Di Fiore PP: Biological and molecular heterogeneity of breast cancers correlates with their cancer stem cell content. Cell. 140:62–73. 2010. View Article : Google Scholar : PubMed/NCBI
21	Vaillant F, Asselin-Labat ML, Shackleton M, Forrest NC, Lindeman GJ and Visvader JE: The mammary progenitor marker CD61/beta3 integrin identifies cancer stem cells in mouse models of mammary tumorigenesis. Cancer Res. 68:7711–7717. 2008. View Article : Google Scholar : PubMed/NCBI
22	Lim E, Vaillant F, Wu D, Forrest NC, Pal B, Hart AH, Asselin-Labat ML, Gyorki DE, Ward T, Partanen A, et al: Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nat Med. 15:907–913. 2009. View Article : Google Scholar : PubMed/NCBI
23	Bhan A, Hussain I, Ansari KI, Bobzean SA, Perrotti LI and Mandal SS: Histone methyltransferase EZH2 is transcriptionally induced by estradiol as well as estrogenic endocrine disruptors bisphenol-A and diethylstilbestrol. J Mol Biol. 426:3426–3441. 2014. View Article : Google Scholar : PubMed/NCBI
24	Li X, Gonzalez ME, Toy K, Filzen T, Merajver SD and Kleer CG: Targeted overexpression of EZH2 in the mammary gland disrupts ductal morphogenesis and causes epithelial hyperplasia. Am J Pathol. 175:1246–1254. 2009. View Article : Google Scholar : PubMed/NCBI
25	Ding L, Erdmann C, Chinnaiyan AM, Merajver SD and Kleer CG: Identification of EZH2 as a molecular marker for a precancerous state in morphologically normal breast tissues. Cancer Res. 66:4095–4099. 2006. View Article : Google Scholar : PubMed/NCBI
26	Ding L and Kleer CG: Enhancer of Zeste 2 as a marker of preneoplastic progression in the breast. Cancer Res. 66:9352–9355. 2006. View Article : Google Scholar : PubMed/NCBI
27	Kleer CG, Cao Q, Varambally S, Shen R, Ota I, Tomlins SA, Ghosh D, Sewalt RG, Otte AP, Hayes DF, et al: EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc Natl Acad Sci USA. 100:11606–11611. 2003. View Article : Google Scholar : PubMed/NCBI
28	Raaphorst FM, Meijer CJ, Fieret E, Blokzijl T, Mommers E, Buerger H, Packeisen J, Sewalt RA, Otte AP and van Diest PJ: Poorly differentiated breast carcinoma is associated with increased expression of the human polycomb group EZH2 gene. Neoplasia. 5:481–488. 2003. View Article : Google Scholar
29	Kunju LP, Cookingham C, Toy KA, Chen W, Sabel MS and Kleer CG: EZH2 and ALDH-1 mark breast epithelium at risk for breast cancer development. Mod Pathol. 24:786–793. 2011. View Article : Google Scholar : PubMed/NCBI
30	Alford SH, Toy K, Merajver SD and Kleer CG: Increased risk for distant metastasis in patients with familial early-stage breast cancer and high EZH2 expression. Breast Cancer Res Treat. 132:429–437. 2012. View Article : Google Scholar :
31	Hussein YR, Sood AK, Bandyopadhyay S, Albashiti B, Semaan A, Nahleh Z, Roh J, Han HD, Lopez-Berestein G and Ali-Fehmi R: Clinical and biological relevance of enhancer of zeste homolog 2 in triple-negative breast cancer. Hum Pathol. 43:1638–1644. 2012. View Article : Google Scholar : PubMed/NCBI
32	Dong M, Fan XJ, Chen ZH, Wang TT, Li X, Chen J, Lin Q, Wen JY, Ma XK, Wei L, et al: Aberrant expression of enhancer of zeste homologue 2, correlated with HIF-1α, refines relapse risk and predicts poor outcome for breast cancer. Oncol Rep. 32:1101–1107. 2014.PubMed/NCBI
33	Chang CJ, Yang JY, Xia W, Chen CT, Xie X, Chao CH, Woodward WA, Hsu JM, Hortobagyi GN and Hung MC: EZH2 promotes expansion of breast tumor initiating cells through activation of RAF1-β-catenin signaling. Cancer Cell. 19:86–100. 2011. View Article : Google Scholar : PubMed/NCBI
34	Gonzalez ME, Moore HM, Li X, Toy KA, Huang W, Sabel MS, Kidwell KM and Kleer CG: EZH2 expands breast stem cells through activation of NOTCH1 signaling. Proc Natl Acad Sci USA. 111:3098–3103. 2014. View Article : Google Scholar : PubMed/NCBI
35	Reijm EA, Jansen MP, Ruigrok-Ritstier K, van Staveren IL, Look MP, van Gelder ME, Sieuwerts AM, Sleijfer S, Foekens JA and Berns EM: Decreased expression of EZH2 is associated with upregulation of ER and favorable outcome to tamoxifen in advanced breast cancer. Breast Cancer Res Treat. 125:387–394. 2011. View Article : Google Scholar
36	Collett K, Eide GE, Arnes J, Stefansson IM, Eide J, Braaten A, Aas T, Otte AP and Akslen LA: Expression of enhancer of zeste homologue 2 is significantly associated with increased tumor cell proliferation and is a marker of aggressive breast cancer. Clin Cancer Res. 12:1168–1174. 2006. View Article : Google Scholar : PubMed/NCBI
37	Gonzalez ME, Li X, Toy K, DuPrie M, Ventura AC, Banerjee M, Ljungman M, Merajver SD and Kleer CG: Downregulation of EZH2 decreases growth of estrogen receptor-negative invasive breast carcinoma and requires BRCA1. Oncogene. 28:843–853. 2009. View Article : Google Scholar :