Sage Journals: Discover world-class research

Abstract

Introduction

Disease recurrence is an important obstacle in estrogen receptor positive (ER⁺) tamoxifen treated breast carcinoma patients. Tamoxifen resistance-related molecular mechanisms are not fully understood. Alteration in DNA methylation which contributes to transcriptional regulation of cancer-related genes plays a crucial role in tamoxifen response. In the present study, the contribution of promoter methylation and mRNA expression of PAX2 and AIB1 in the development of breast carcinoma and tamoxifen refractory was assessed.

Methods

Methylation specific-high resolution melting (MS-HRM) analysis and Real-time quantitative PCR (RT-qPCR) experiment were performed to analyze the promoter methylation and mRNA expression levels of PAX2 and AIB1 genes in 102 breast tumors and adjacent normal breast specimens.

Results

We indicated that PAX2 expression is decreased in breast tissues due to hypermethylation in its promoter region. Compared to the adjacent normal tissues, the tumors exhibited significantly lower relative mRNA levels of PAX2 and increased expression of AIB1. Aberrant promoter methylation of PAX2 and overexpression of AIB1 was observed in tamoxifen resistance patients compared to the sensitive ones. Cox regression analysis exhibited that the increased promoter methylation status of PAX2 and overexpression of AIB1 remained as unfavorable identifiers which influence patients' survival independently.

Conclusions

Our results revealed that the aberration in PAX2 promoter methylation and AIB1 overexpression are associated with the tamoxifen response in breast carcinoma patients. Further research is needed to demonstrate the potential of using PAX2 and AIB1 expression and their methylation-mediated regulation as predictive or prognostic biomarkers or as a new target therapy for better disease management.

Keywords

Breast cancer tamoxifen resistance PAX2 AIB1 promoter methylation

Get full access to this article

View all access options for this article.

References

Tanic

Milovanovic

Tanic

et al. The impact of PTEN tumor suppressor gene on acquiring resistance to tamoxifen treatment in breast cancer patients. Cancer Biol Ther 2012; 13: 1165–1174.

Zhou

et al. COPS5 amplification and overexpression confers tamoxifen-resistance in ERalpha-positive breast cancer by degradation of NCoR. Nat Commun 2016; 7: 12044–12007.

Lin

Zhang

and Manson

JE.

Predicting adherence to tamoxifen for breast cancer adjuvant therapy and prevention. Cancer Prev Res (Phila) 2011; 4: 1360–1365.

Schiff

Massarweh

Shou

et al. Breast cancer endocrine resistance: how growth factor signaling and estrogen receptor coregulators modulate response. Clin Cancer Res 2003; 9: 447S–454S.

Kutomi

Mizuguchi

Satomi

et al. Current status of the prognostic molecular biomarkers in breast cancer: a systematic review. Oncol Lett 2017; 13: 1491–1498.

Kharbanda

Rajabi

Jin

et al. Oncogenic MUC1-C promotes tamoxifen resistance in human breast cancer. Mol Cancer Res 2013; 11: 714–723.

Fernandez-Cuesta

Anaganti

Hainaut

et al. p53 status influences response to tamoxifen but not to fulvestrant in breast cancer cell lines. Int J Cancer 2011; 128: 1813–1821.

Thomas

Thurn

Bicaku

et al. Addition of a histone deacetylase inhibitor redirects tamoxifen-treated breast cancer cells into apoptosis, which is opposed by the induction of autophagy. Breast Cancer Res Treat 2011; 130: 437–447.

Jahangiri

Mosaffa

EmamiRazavi

et al. Increased expression of gankyrin and stemness factor oct-4 are associated with unfavorable clinical outcomes and poor benefit of tamoxifen in breast carcinoma patients. Pathol Oncol Res 2019; 26: 12–20.

10.

Higgins

and Stearns

Understanding resistance to tamoxifen in hormone receptor-positive breast cancer. Clin Chem 2009; 55: 1453–1455.

11.

Hurtado

Holmes

Geistlinger

et al. Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen. Nature 2008; 456: 663–666.

12.

Blake

and Ziman

MR.

Pax genes: regulators of lineage specification and progenitor cell maintenance. Development 2014; 141: 737–751.

13.

and Eccles

MR.

PAX genes in cancer; friends or foes?

Front Genet 2012; 3: 6.

14.

Robson

and Eccles

MR.

A PANorama of PAX genes in cancer and development. Nat Rev Cancer 2006; 6: 52–62.

15.

Fiorito

Katika

and Hurtado

Cooperating transcription factors mediate the function of estrogen receptor. Chromosoma 2013; 122: 1–12.

16.

Chang

and Wu

The role of AIB1 in breast cancer. Oncol Lett 2012; 4: 588–594.

17.

Louie

Zou

Rabinovich

et al. ACTR/AIB1 functions as an E2F1 coactivator to promote breast cancer cell proliferation and antiestrogen resistance. Mol Cell Biol 2004; 24: 5157–5171.

18.

Shi

Liu

Sui

et al. Frequent amplification of AIB1, a critical oncogene modulating major signaling pathways, is associated with poor survival in gastric cancer. Oncotarget 2015; 6: 14344–14359.

19.

Badia

Oliva

Balaguer

et al. Tamoxifen resistance and epigenetic modifications in breast cancer cell lines. Curr Med Chem 2007; 14: 3035–3045.

20.

Abdel-Hafiz

HA.

Epigenetic mechanisms of tamoxifen resistance in luminal breast cancer. Diseases (Basel, Switzerland) 2017; 5: 16.

21.

Zhu

and Yao

Use of DNA methylation for cancer detection: promises and challenges. Int J Biochem Cell Biol 2009; 41: 147–154.

22.

Das

and Singal

DNA methylation and cancer. J Clin Oncol 2004; 22: 4632–4642.

23.

http://Aug2020.archive.ensembl.org/Homo_sapiens/Gene/Sequence?db=core.g=ENSG00000075891;r=10:100735603-100829944

24.

http://Aug2020.archive.ensembl.org/Homo_sapiens/Gene/Sequence?db=core;g=ENSG00000253271;r=8:117055818-117056145;t=ENST00000522976

25.

Wojdacz

Borgbo

and Hansen

LL.

Primer design versus PCR bias in methylation independent PCR amplifications. Epigenetics 2009; 4: 231–234.

26.

Bussolati

Bruno

Grange

et al. Isolation of renal progenitor cells from adult human kidney. Am J Pathol 2005; 166: 545–555.

27.

Livak

and Schmittgen

TD.

Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 2001; 25: 402–408.

28.

Jahangiri

Mosaffa

Emami Razavi

et al. Altered DNA methyltransferases promoter methylation and mRNA expression are associated with tamoxifen response in breast tumors. J Cell Physiol 2018; 233: 7305–7319.

29.

Jahangiri

Jamialahmadi

Gharib

et al. Expression and clinicopathological significance of DNA methyltransferase 1, 3A and 3B in tamoxifen-treated breast cancer patients. Gene 2019; 685: 24–31.

30.

Eccles

Legge

et al. PAX genes in development and disease: the role of PAX2 in urogenital tract development. Int J Dev Biol 2002; 46: 535–544.

31.

Al-Hujaily

Tang

Yao

et al. Divergent roles of PAX2 in the etiology and progression of ovarian cancer. Cancer Prev Res (Phila) 2015; 8: 1163–1173.

32.

Liu

Gao

Huan

et al. Upregulation of PAX2 promotes the metastasis of esophageal cancer through interleukin-5. Cell Physiol Biochem 2015; 35: 740–754.

33.

Bouras

Southey

and Venter

DJ.

Overexpression of the steroid receptor coactivator AIB1 in breast cancer correlates with the absence of estrogen and progesterone receptors and positivity for p53 and HER2/neu. Cancer Res 2001; 61: 903–907.

34.

Henke

Haddad

Kim

et al. Overexpression of the nuclear receptor coactivator AIB1 (SRC-3) during progression of pancreatic adenocarcinoma. Clin Cancer Res 2004; 10: 6134–6142.

35.

Zhou

Guan

et al. Amplified in breast cancer 1 promotes colorectal cancer progression through enhancing notch signaling. Oncogene 2015; 34: 3935–3945.

36.

Chen

Liang

et al. Hypomethylation-linked activation of PAX2 mediates tamoxifen-stimulated endometrial carcinogenesis. Nature 2005; 438: 981–987.

37.

Jia

Wang

et al. DNA methylation promotes paired box 2 expression via myeloid zinc finger 1 in endometrial cancer. Oncotarget 2016; 7: 84785–84797.

38.

Patrício

Ramalho-Carvalho

Costa-Pinheiro

et al. Deregulation of PAX2 expression in renal cell tumours: mechanisms and potential use in differential diagnosis. J Cell Mol Med 2013; 17: 1048–1058.

39.

and Shang

Regulation of SRC family coactivators by post-translational modifications. Cell Signal 2007; 19: 1101–1112.

40.

O’Hara

Vareslija

McBryan

et al. AIB1:ERalpha transcriptional activity is selectively enhanced in aromatase inhibitor-resistant breast cancer cells. Clin Cancer Res 2012; 18: 3305–3315.

41.

Jahangiri

Mosaffa

Gharib

et al. PAX2 expression is correlated with better survival in tamoxifen-treated breast carcinoma patients. Tissue Cell 2018; 52: 135–142.

42.

Alkner

Bendahl

Grabau

et al. The role of AIB1 and PAX2 in primary breast cancer: validation of AIB1 as a negative prognostic factor. Ann Oncol 2013; 24: 1244–1252.

43.

Lee

Song

et al. Expression of AIB1 protein as a prognostic factor in breast cancer. World J Surg Oncol 2011; 9: 139.

44.

Zhao

et al. Overexpression of AIB1 negatively affects survival of surgically resected non-small-cell lung cancer patients. Ann Oncol 2010; 21: 1675–1681.

45.

Chen

Wang

Zhang

et al. AIB1 genomic amplification predicts poor clinical outcomes in female glioma patients. J Cancer 2016; 7: 2052–2060.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.41 MB

0.13 MB

0.20 MB

0.12 MB

0.15 MB

0.13 MB

0.15 MB

0.14 MB

PAX2 promoter methylation and AIB1 overexpression promote tamoxifen resistance in breast carcinoma patients

Abstract

Introduction

Methods

Results

Conclusions

Keywords

Get full access to this article

References

Supplementary Material