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Breast Cancer Research
Published in: Breast Cancer Research 6/2010

Open Access 01-12-2010 | Research article

Cystatin M loss is associated with the losses of estrogen receptor, progesterone receptor, and HER4 in invasive breast cancer

Authors: Eunkyung Ko, Seong-Eun Park, Eun Yoon Cho, Yujin Kim, Jung-Ah Hwang, Yeon-Su Lee, Seok Jin Nam, Saik Bang, Joobae Park, Duk-Hwan Kim

Published in: Breast Cancer Research | Issue 6/2010

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Abstract

Introduction

This study was aimed at understanding the clinicopathological significance of cystatin M loss, and investigating possible factors responsible for cystatin M loss in breast cancer.

Methods

The expression of estrogen receptor (ER), progesterone receptor (PR), HER2, HER4, and cystatin M was retrospectively analyzed using immunohistochemistry in 117 patients with ductal carcinoma in situ (DCIS) and in 175 patients with invasive breast cancer (IBC). The methylation status of CST6 gene encoding cystatin M was evaluated using methylation-specific polymerase chain reaction (PCR) in formalin-fixed paraffin-embedded tissues from 292 participants and using pyrosequencing in fresh-frozen tumor and matched normal tissues from 51 IBC patients.

Results

Cystatin M loss was found in 9 (8%) of 117 patients with DCIS and in 99 (57%) of 175 with invasive breast cancer (IBC) (P < 0.0001). Cystatin M loss was found in 58 (57%) of 101 HER2-negative IBCs and in 41 (55%) of 74 HER2-positive IBCs, and this difference was not statistically significant (P = 0.97). However, cystatin M loss was significantly associated with the loss of ER (P = 0.01), PR (P = 0.002), and HER4 (P = 0.003) in IBCs. Cystatin M loss occurred in 34 (76%) of the 45 HER4-negative IBCs and in 65 (50%) of the 130 HER4-positive IBCs. Multivariate analysis showed that cystatin M loss occurred at a 3.57 times (95% CI = 1.28 to 9.98; P = 0.01) higher prevalence in the triple-negative IBCs of ER, PR, and HER4 than in other subtypes, after adjusting for age. The quantity of CST6 methylation was associated with ER loss (P = 0.0002) in IBCs but not with the loss of PR (P = 0.64) or HER4 (P = 0.87).

Conclusions

The present study suggests that cystatin M loss may be associated with the losses of ER, PR, and HER4 in IBC.
Appendix
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Literature
1.
Ernster VL, Ballard-Barbash R, Barlow WE, Zheng Y, Weaver DL, Cutter G, Yankaskas BC, Rosenberg R, Carney PA, Kerlikowske K, Taplin SH, Urban N, Geller BM: Detection of ductal carcinoma in situ in women undergoing screening mammography. J Natl Cancer Inst. 2002, 94: 1546-1554.CrossRefPubMed
2.
Leonard GD, Swain SM: Ductal carcinoma in situ, complexities and challenges. J Natl Cancer Inst. 2004, 96: 906-920. 10.1093/jnci/djh164.CrossRefPubMed
3.
Sotiropoulou G, Anisowicz A, Sager R: Identification, cloning, and characterization of cystatin M, a novel cysteine proteinase inhibitor, down-regulated in breast cancer. J Biol Chem. 1997, 272: 903-910. 10.1074/jbc.272.2.903.CrossRefPubMed
4.
Zhang J, Shridhar R, Dai Q, Song J, Barlow SC, Yin L, Sloane BF, Miller FR, Meschonat C, Li BD, Abreo F, Keppler D: Cystatin m: a novel candidate tumor suppressor gene for breast cancer. Cancer Res. 2004, 64: 6957-6964. 10.1158/0008-5472.CAN-04-0819.CrossRefPubMed
5.
Rivenbark AG, Jones WD, Risher JD, Coleman WB: DNA methylation-dependent epigenetic regulation of gene expression in MCF-7 breast cancer cells. Epigenetics. 2006, 1: 32-44. 10.4161/epi.1.1.2358.CrossRefPubMed
6.
Schagdarsurengin U, Pfeifer GP, Dammann R: Frequent epigenetic inactivation of cystatin M in breast carcinoma. Oncogene. 2007, 26: 3089-3094. 10.1038/sj.onc.1210107.CrossRefPubMed
7.
Song J, Jie C, Polk P, Shridhar R, Clair T, Zhang J, Yin L, Keppler D: The candidate tumor suppressor CST6 alters the gene expression profile of human breast carcinoma cells: down-regulation of the potent mitogenic, motogenic, and angiogenic factor autotaxinv. Biochem Biophys Res Commun. 2006, 340: 175-182. 10.1016/j.bbrc.2005.11.171.CrossRefPubMed
8.
Shridhar R, Zhang J, Song J, Booth BA, Kevil CG, Sotiropoulou G, Sloane BF, Keppler D: Cystatin M suppresses the malignant phenotype of human MDA-MB-435 S cells. Oncogene. 2004, 23: 2206-2215. 10.1038/sj.onc.1207340.CrossRefPubMed
9.
Leu YW, Yan PS, Fan M, Jin VX, Liu JC, Curran EM, Welshons WV, Wei SH, Davuluri RV, Plass C, Nephew KP, Huang TH: Loss of estrogen receptor signaling triggers epigenetic silencing of downstream targets in breast cancer. Cancer Res. 2004, 64: 8184-8192. 10.1158/0008-5472.CAN-04-2045.CrossRefPubMed
10.
Knowlden JM, Gee JM, Seery LT, Farrow L, Gullick WJ, Ellis IO, Blamey RW, Robertson JF, Nicholson RI: c-erbB3 and c-erbB4 expression is a feature of the endocrine responsive phenotype in clinical breast cancer. Oncogene. 1998, 17: 1949-1957. 10.1038/sj.onc.1202107.CrossRefPubMed
11.
Suo Z, Berner HS, Risberg B, Karlsson MG, Nesland JM: Estrogen receptor-alpha and C-ERBB-4 expression in breast carcinomas. Virchows Arch. 2001, 439: 62-69. 10.1007/s004280000392.CrossRefPubMed
12.
Barnes NL, Khavari S, Boland GP, Cramer A, Knox WF, Bundred NJ: Absence of HER4 expression predicts recurrence of ductal carcinoma in situ of the breast. Clin Cancer Res. 2005, 11: 2163-2168. 10.1158/1078-0432.CCR-04-1633.CrossRefPubMed
13.
Junttila TT, Sundvall M, Lundin M, Lundin J, Tanner M, Härkönen P, Joensuu H, Isola J, Elenius K: Cleavable ErbB4 isoform in estrogen receptor-regulated growth of breast cancer cells. Cancer Res. 2005, 65: 1384-1393. 10.1158/0008-5472.CAN-04-3150.CrossRefPubMed
14.
Zhu Y, Sullivan LL, Nair SS, Williams CC, Pandey AK, Marrero L, Vadlamudi RK, Jones FE: Coregulation of estrogen receptor by ERBB4/HER4 establishes a growth-promoting autocrine signal in breast tumor cells. Cancer Research. 2006, 66: 7991-7998. 10.1158/0008-5472.CAN-05-4397.CrossRefPubMed
15.
Torhorst J, Bucher C, Kononen J, Haas P, Zuber M, Kochli OR, Mross F, Dieterich H, Moch H, Mihatsch M, Kallioniemi OP, Sauter G: Tissue microarrays for rapid linking of molecular changes to clinical endpoints. Am J Pathol. 2001, 159: 2249-2256.CrossRefPubMedPubMedCentral
16.
Herman JG, Graff JR, Myöhänen S, Nelkin BD, Baylin SB: Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA. 1996, 93: 9821-9826. 10.1073/pnas.93.18.9821.CrossRefPubMedPubMedCentral
17.
Hewitt SC, Korach KS: Progesterone action and responses in the alpha ERKO mouse. Steroids. 2000, 65: 551-557. 10.1016/S0039-128X(00)00113-6.CrossRefPubMed
18.
Richer JK, Jacobsen BM, Manning NG, Abel MG, Wolf DM, Horwitz KB: Differential gene regulation by the two progesterone receptor isoforms in human breast cancer cells. J Biol Chem. 2002, 277: 5209-5218. 10.1074/jbc.M110090200.CrossRefPubMed
19.
Jacobsen BM, Richer JK, Schittone SA, Horwitz KB: New human breast cancer cells to study progesterone receptor isoform ratio effects and ligand-independent gene regulation. J Biol Chem. 2002, 277: 27793-27800. 10.1074/jbc.M202584200.CrossRefPubMed
20.
Rio C, Buxbaum JD, Peschon JJ, Corfas G: Tumor necrosis factor-a-convertingenzym e is required for cleavage of erbB4/HER4. J Biol Chem. 2000, 275: 10379-10387. 10.1074/jbc.275.14.10379.CrossRefPubMed
21.
Ni C-Y, Murphy MP, Golde TE, Carpenter G: γ-secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase. Science. 2001, 294: 2179-2181. 10.1126/science.1065412.CrossRefPubMed
22.
Lee HJ, Jung KM, Huang YZ, Bennett LB, Lee JS, Mei L, Kim TW: Presenilin-dependent γ-secretase-like intramembrane cleavage of ErbB4. J Biol Chem. 2002, 277: 6318-6323. 10.1074/jbc.M110371200.CrossRefPubMed
23.
Elenius K, Choi CJ, Paul S, Santiestevan E, Nishi E, Klagsbrun M: Characterization of a naturally occurring ErbB4 isoform that does not bind or activate phosphatidyl inositol 3-kinase. Oncogene. 1999, 18: 2607-2615. 10.1038/sj.onc.1202612.CrossRefPubMed
24.
Long W, Wagner KU, Lloyd KC, Binart N, Shillingford JM, Hennighausen L, Jones FE: Impaired differentiation and lactational failure of Erbb4-deficient mammary glands identify ERBB4 as an obligate mediator of STAT5. Development. 2003, 130: 5257-5268. 10.1242/dev.00715.CrossRefPubMed
25.
26.
Cheung E, Acevedo ML, Cole PA, Kraus WL: Altered pharmacology and distinct coactivator usage for estrogen receptor-dependent transcription through activating protein-1. Proc Natl Acad Sci USA. 2005, 102: 559-564. 10.1073/pnas.0407113102.CrossRefPubMedPubMedCentral
27.
Schultz JR, Petz LN, Nardulli AM: Cell- and ligand-specific regulation of promoters containing activator protein-1 and Sp1 sites by estrogen receptors alpha and beta. J Biol Chem. 2005, 280: 347-354.CrossRefPubMed
Metadata
Title
Cystatin M loss is associated with the losses of estrogen receptor, progesterone receptor, and HER4 in invasive breast cancer
Authors
Eunkyung Ko
Seong-Eun Park
Eun Yoon Cho
Yujin Kim
Jung-Ah Hwang
Yeon-Su Lee
Seok Jin Nam
Saik Bang
Joobae Park
Duk-Hwan Kim
Publication date
01-12-2010
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 6/2010
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr2783

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