Grhl2 Determines the Epithelial Phenotype of Breast Cancers and Promotes Tumor Progression

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2013 Jan 4

PMID 23284647

Citations 67

Authors

Xiaoyu Xiang

Zhongbin Deng

Xiaoying Zhuang

Songwen Ju

Jingyao Mu

Hong Jiang

Lifeng Zhang

Jun Yan

Donald Miller

Huang-Ge Zhang

Affiliations

Soon will be listed here.

Abstract

Until now the essential transcription factor that determines the epithelial phenotype of breast cancer has not been identified and its role in epithelial-to-mesenchymal transition (EMT) and tumor progression remain unclear. Here, by analyzing large expression profiles of human breast cancer cells, we found an extraordinary correlation between the expression of Grainyhead transcription factor Grhl2 and epithelial marker E-cadherin. Knockdown of Grhl2 expression by shRNA in human mammary epithelial cell MCF10A leads to down-regulation of E-cadherin and EMT. Grhl2 is down-regulated in disseminated cancer cells that have undergone EMT, and over-expression of Grhl2 is sufficient to induce epithelial gene expression. Large clinical datasets reveal that expression of Grhl2 is significantly associated with poor relapse free survival and increased risk of metastasis in breast cancer patients. In mouse models, over-expression of Grhl2 significantly promotes tumor growth and metastasis. Further testing of several Grhl2 regulated genes leads to the same conclusions that the tumorigenic and metastatic potentials of tumor cells are linked to epithelial phenotype but not mesenchymal phenotype. In conclusion, our findings indicate that Grhl2 plays an essential role in the determination of epithelial phenotype of breast cancers, EMT and tumor progression.

Citing Articles

MORF4L2 induces immunosuppressive microenvironment and immunotherapy resistance through GRHL2/MORF4L2/H4K12Ac/CSF1 axis in triple-negative breast cancer.

Sui X, Cao S, Song X, Liu X, Chen C, Yan Q Biomark Res. 2025; 13(1):6.

PMID: 39780291 PMC: 11715975. DOI: 10.1186/s40364-024-00719-1.

Luminal epithelial cells integrate variable responses to aging into stereotypical changes that underlie breast cancer susceptibility.

Sayaman R, Miyano M, Carlson E, Senapati P, Zirbes A, Shalabi S Elife. 2024; 13.

PMID: 39545637 PMC: 11723586. DOI: 10.7554/eLife.95720.

GRHL2 regulates keratinocyte EMT-MET dynamics and scar formation during cutaneous wound healing.

Chen T, Zhang B, Xie H, Huang C, Wu Q Cell Death Dis. 2024; 15(10):748.

PMID: 39402063 PMC: 11473813. DOI: 10.1038/s41419-024-07121-7.

Elevated GRHL2 Imparts Plasticity in ER-Positive Breast Cancer Cells.

Zheng C, Allen K, Liu T, Solodin N, Meyer M, Salem K Cancers (Basel). 2024; 16(16).

PMID: 39199676 PMC: 11353109. DOI: 10.3390/cancers16162906.

Development of an epigenetic clock resistant to changes in immune cell composition.

Tomusiak A, Floro A, Tiwari R, Riley R, Matsui H, Andrews N Commun Biol. 2024; 7(1):934.

PMID: 39095531 PMC: 11297166. DOI: 10.1038/s42003-024-06609-4.

References

Korpal M, Ell B, Buffa F, Ibrahim T, Blanco M, Celia-Terrassa T . Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization. Nat Med. 2011; 17(9):1101-8. PMC: 3169707. DOI: 10.1038/nm.2401. View

Peinado H, Olmeda D, Cano A . Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype?. Nat Rev Cancer. 2007; 7(6):415-28. DOI: 10.1038/nrc2131. View

Gibbons D, Lin W, Creighton C, Rizvi Z, Gregory P, Goodall G . Contextual extracellular cues promote tumor cell EMT and metastasis by regulating miR-200 family expression. Genes Dev. 2009; 23(18):2140-51. PMC: 2751985. DOI: 10.1101/gad.1820209. View

Yori J, Johnson E, Zhou G, Jain M, Keri R . Kruppel-like factor 4 inhibits epithelial-to-mesenchymal transition through regulation of E-cadherin gene expression. J Biol Chem. 2010; 285(22):16854-63. PMC: 2878056. DOI: 10.1074/jbc.M110.114546. View

Celia-Terrassa T, Meca-Cortes O, Mateo F, Martinez de Paz A, Rubio N, Arnal-Estape A . Epithelial-mesenchymal transition can suppress major attributes of human epithelial tumor-initiating cells. J Clin Invest. 2012; 122(5):1849-68. PMC: 3366719. DOI: 10.1172/JCI59218. View

Chiu H, Szucsik J, Georgas K, Jones J, Rumballe B, Tang D . Comparative gene expression analysis of genital tubercle development reveals a putative appendicular Wnt7 network for the epidermal differentiation. Dev Biol. 2010; 344(2):1071-87. PMC: 3154616. DOI: 10.1016/j.ydbio.2010.05.495. View

Thiery J, Acloque H, Huang R, Nieto M . Epithelial-mesenchymal transitions in development and disease. Cell. 2009; 139(5):871-90. DOI: 10.1016/j.cell.2009.11.007. View

Saeed A, Bhagabati N, Braisted J, Liang W, Sharov V, Howe E . TM4 microarray software suite. Methods Enzymol. 2006; 411:134-93. DOI: 10.1016/S0076-6879(06)11009-5. View

Hajra K, Fearon E . The SLUG zinc-finger protein represses E-cadherin in breast cancer. Cancer Res. 2002; 62(6):1613-8. View

10.

Yu Z, Bhandari A, Mannik J, Pham T, Xu X, Andersen B . Grainyhead-like factor Get1/Grhl3 regulates formation of the epidermal leading edge during eyelid closure. Dev Biol. 2008; 319(1):56-67. PMC: 2494567. DOI: 10.1016/j.ydbio.2008.04.001. View

11.

Santisteban M, Reiman J, Asiedu M, Behrens M, Nassar A, Kalli K . Immune-induced epithelial to mesenchymal transition in vivo generates breast cancer stem cells. Cancer Res. 2009; 69(7):2887-95. PMC: 2664865. DOI: 10.1158/0008-5472.CAN-08-3343. View

12.

Xiang X, Zhuang X, Ju S, Zhang S, Jiang H, Mu J . miR-155 promotes macroscopic tumor formation yet inhibits tumor dissemination from mammary fat pads to the lung by preventing EMT. Oncogene. 2011; 30(31):3440-53. PMC: 4139014. DOI: 10.1038/onc.2011.54. View

13.

Mani S, Guo W, Liao M, Eaton E, Ayyanan A, Zhou A . The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008; 133(4):704-15. PMC: 2728032. DOI: 10.1016/j.cell.2008.03.027. View

14.

Filant J, Zhou H, Spencer T . Progesterone inhibits uterine gland development in the neonatal mouse uterus. Biol Reprod. 2012; 86(5):146, 1-9. PMC: 3364926. DOI: 10.1095/biolreprod.111.097089. View

15.

Winuthayanon W, Hewitt S, Orvis G, Behringer R, Korach K . Uterine epithelial estrogen receptor α is dispensable for proliferation but essential for complete biological and biochemical responses. Proc Natl Acad Sci U S A. 2010; 107(45):19272-7. PMC: 2984169. DOI: 10.1073/pnas.1013226107. View

16.

Bhat-Nakshatri P, Appaiah H, Ballas C, Pick-Franke P, Goulet Jr R, Badve S . SLUG/SNAI2 and tumor necrosis factor generate breast cells with CD44+/CD24- phenotype. BMC Cancer. 2010; 10:411. PMC: 3087321. DOI: 10.1186/1471-2407-10-411. View

17.

Visvader J . Keeping abreast of the mammary epithelial hierarchy and breast tumorigenesis. Genes Dev. 2009; 23(22):2563-77. PMC: 2779757. DOI: 10.1101/gad.1849509. View

18.

Comijn J, Berx G, Vermassen P, Verschueren K, van Grunsven L, Bruyneel E . The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Mol Cell. 2001; 7(6):1267-78. DOI: 10.1016/s1097-2765(01)00260-x. View

19.

Morel A, Hinkal G, Thomas C, Fauvet F, Courtois-Cox S, Wierinckx A . EMT inducers catalyze malignant transformation of mammary epithelial cells and drive tumorigenesis towards claudin-low tumors in transgenic mice. PLoS Genet. 2012; 8(5):e1002723. PMC: 3359981. DOI: 10.1371/journal.pgen.1002723. View

20.

Werth M, Walentin K, Aue A, Schonheit J, Wuebken A, Pode-Shakked N . The transcription factor grainyhead-like 2 regulates the molecular composition of the epithelial apical junctional complex. Development. 2010; 137(22):3835-45. DOI: 10.1242/dev.055483. View