Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Breast Cancer Research and Treatment
Published in: Breast Cancer Research and Treatment 1/2014

01-07-2014 | Preclinical study

Hypomethylation of the MMP7 promoter and increased expression of MMP7 distinguishes the basal-like breast cancer subtype from other triple-negative tumors

Authors: Steven T. Sizemore, Gina M. Sizemore, Christine N. Booth, Cheryl L. Thompson, Paula Silverman, Gurkan Bebek, Fadi W. Abdul-Karim, Stefanie Avril, Ruth A. Keri

Published in: Breast Cancer Research and Treatment | Issue 1/2014

Login to get access

Abstract

Identification of novel targets for the treatment of basal-like breast cancer is essential for improved outcomes in patients with this disease. This study investigates the association of MMP7 expression and MMP7 promoter methylation with subtype and outcome in breast cancer patient cohorts. Immunohistochemical analysis was performed on a breast cancer tissue microarray and validated in independent histological samples. MMP7 expression significantly correlated with patient age, tumor size, triple-negative (TN) status, and recurrence. Analysis of publically available datasets confirmed MMP7 gene expression as a prognostic marker of breast cancer metastasis, particularly metastasis to the brain and lungs. Methylation of the MMP7 promoter was assessed by methylation-specific PCR in a panel of breast cancer cell lines and patient tumor samples. Hypomethylation of the MMP7 promoter significantly correlated with TN status in DNA from patient tumor samples, and this association was confirmed using The Cancer Genome Atlas (TCGA) dataset. Evaluation of a panel of breast cancer cell lines and data from the Curtis and TCGA breast carcinoma datasets revealed that elevated MMP7 expression and MMP7 promoter hypomethylation are specific biomarkers of the basal-like molecular subtype which shares considerable, but not complete, overlap with the clinical TN subtype. Importantly, MMP7 expression was identified as an independent predictor of pathological complete response in a large breast cancer patient cohort. Combined, these data suggest that MMP7 expression and MMP7 promoter methylation may be useful as prognostic biomarkers. Furthermore, MMP7 expression and promoter methylation analysis may be effective mechanisms to distinguish basal-like breast cancers from other triple-negative subtypes. Finally, these data implicate MMP7 as a potential therapeutic target for the treatment of basal-like breast cancers.
Appendix
Available only for authorised users
Literature
1.
Hua H, Li M, Luo T, Yin Y, Jiang Y (2011) Matrix metalloproteinases in tumorigenesis: an evolving paradigm. Cell Mol Life Sci 68(23):3853–3868PubMedCrossRef
2.
Kleiner DE, Stetler-Stevenson WG (1999) Matrix metalloproteinases and metastasis. Cancer Chemother Pharmacol 43(Suppl):S42–S51PubMedCrossRef
3.
Gialeli C, Theocharis AD, Kletsas D, Tzanakakis GN, Karamanos NK (2013) Expression of matrix macromolecules and functional properties of EGF-responsive colon cancer cells are inhibited by panitumumab. Invest New Drugs 31(3):516–524PubMedCrossRef
4.
Noe V, Fingleton B, Jacobs K, Crawford HC, Vermeulen S, Steelant W, Bruyneel E, Matrisian LM, Mareel M (2001) Release of an invasion promoter E-cadherin fragment by matrilysin and stromelysin-1. J Cell Sci 114(Pt 1):111–118PubMed
5.
Rucci N, Sanita P, Angelucci A (2011) A Roles of metalloproteases in metastatic niche. Curr Mol Med 11(8):609–622PubMedCrossRef
6.
Yu Q, Stamenkovic I (2000) Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev 14(2):163–176PubMedCentralPubMed
7.
Yu WH, Woessner JF Jr, McNeish JD, Stamenkovic I (2002) CD44 anchors the assembly of matrilysin/MMP-7 with heparin-binding epidermal growth factor precursor and ErbB4 and regulates female reproductive organ remodeling. Genes Dev 16(3):307–323PubMedCentralPubMedCrossRef
8.
Heppner KJ, Matrisian LM, Jensen RA, Rodgers WH (1996) Expression of most matrix metalloproteinase family members in breast cancer represents a tumor-induced host response. Am J Path 149(1):273–282PubMedCentralPubMed
9.
Fang YJ, Pan ZZ, Li LR, Lu ZH, Zhang LY, Wan DS (2009) MMP7 expression regulated by endocrine therapy in ERbeta-positive colon cancer cells. J Exp Clin Cancer Res 28:132PubMedCentralPubMedCrossRef
10.
Fukuda A, Wang SC, Morris JPt, Folias AE, Liou A, Kim GE, Akira S, Boucher KM, Firpo MA, Mulvihill SJ, Hebrok M (2011) Stat3 and MMP7 contribute to pancreatic ductal adenocarcinoma initiation and progression. Cancer Cell 19(4):441–455PubMedCentralPubMedCrossRef
11.
Gentner B, Wein A, Croner RS, Zeittraeger I, Wirtz RM, Roedel F, Dimmler A, Dorlaque L, Hohenberger W, Hahn EG, Brueckl WM (2009) Differences in the gene expression profile of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in primary colorectal tumors and their synchronous liver metastases. Anticancer Res 29(1):67–74PubMed
12.
Tonini G, Pantano F, Vincenzi B, Gabbrielli A, Coppola R, Santini D (2007) Molecular prognostic factors in patients with pancreatic cancer. Expert Opin Ther Targets 11(12):1553–1569PubMedCrossRef
13.
Fang YJ, Lu ZH, Wang F, Wu XJ, Li LR, Zhang LY, Pan ZZ, Wan DS (2010) Prognostic impact of ERβ and MMP7 expression on overall survival in colon cancer. Tumour Biol 31(6):651–658PubMedCrossRef
14.
Huang Y, Yu H, Lei H, Xie C, Zhong Y (2014) Matrix metalloproteinase 7 is a usefulmarker for 5-fluorouracil-based adjuvant chemotherapy in stage II and stage III colorectal cancer patients. Med Oncol 31:824PubMedCrossRef
15.
Gallego R, Codony-Servat J, García-Albéniz X, Carcereny E, Longarón R, Oliveras A, Tosca M, Augé JM, Gascón P, Maurel J (2009) Serum IGF-I, IGFBP-3, and matrix metalloproteinase-7 levels and acquired chemo-resistance in advanced colorectal cancer. Endocr Relat Cancer 16(1):1412–1420
16.
Fang YJ, Lu ZH, Wang GQ, Pan ZZ, Zhou ZW, Yun JP, Zhang MF, Wan DS (2009) Elevated expressions of MMP7, TROP2, and survivin are associated with survival, disease recurrence, and liver metastasis of colon cancer. Int J Colorectal Dis 24(8):875–884PubMedCrossRef
17.
Wu J, Guan X, Zhang K, Li YT, Bai P, Wu J (2013) A/G polymorphism of matrix metalloproteinase 7 gene promoter region and cancer risk: a meta-analysis. Biomed Rep 1(5):792–796PubMedCentralPubMed
18.
Ke P, Wu ZD, Wen HS, Ying MX, Long HC, Qing LG (2013) Current evidence on associations between the MMP-7 (-181A > G) polymorphism and digestive system cancer risk. Asian Pac J Cancer Prev 14(4):2269–2272PubMedCrossRef
19.
Liu D, Guo H, Li Y, Xu X, Yang K, Bai Yc (2012) Association between polymorphisms in the promoter regions of matrix metalloproteinases (MMPs) and risk of cancer metastasis: a meta-analysis. PLoS ONE 7(2):e31251PubMedCentralPubMedCrossRef
20.
Saarialho-Kere UK, Crouch EC, Parks WC (1995) Matrix metalloproteinase matrilysin is constitutively expressed in adult human exocrine epithelium. J Invest Dermatol 105(2):190–196PubMedCrossRef
21.
Yuan G, Qian L, Shi M, Lu F, Li D, Hu M, Yu M, Shen B, Guo N (2008) HER2-dependent MMP-7 expression is mediated by activated STAT3. Cell Signal 20(7):1284–1291PubMedCrossRef
22.
Yuan G, Qian L, Song L, Shi M, Li D, Yu M, Hu M, Shen B, Guo N (2008) Heregulin-beta promotes matrix metalloproteinase-7 expression via HER2-mediated AP-1 activation in MCF-7 cells. Mol Cell Biochem 318(1–2):73–79PubMedCrossRef
23.
Sizemore ST, Keri RA (2012) The forkhead box transcription factor FOXC1 promotes breast cancer invasion by inducing matrix metalloprotease 7 (MMP7) expression. J Biol Chem 287(29):24631–24640PubMedCentralPubMedCrossRef
24.
Bertucci F, Finetti P, Cervera N, Esterni B, Hermitte F, Viens P, Birnbaum D (2008) How basal are triple-negative breast cancers? Int J Cancer 123(1):236–240PubMedCrossRef
25.
Valentin MD, da Silva SD, Privat M, Alaoui-Jamali M, Bignon YJ (2012) Molecular insights on basal-like breast cancer. Breast Cancer Res Treat 134(1):21–30PubMedCrossRef
26.
Parker JS, Mullins M, Cheang MC, Leung S, Voduc D, Vickery T, Davies S, Fauron C, He X, Hu Z, Quackenbush JF, Stijleman IJ, Palazzo J, Marron JS, Nobel AB, Mardis E, Nielsen TO, Ellis MJ, Perou CM, Bernard PS (2009) Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol 27(8):1160–1167PubMedCentralPubMedCrossRef
27.
Sørlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, Thorsen T, Quist H, Matese JC, Brown PO, Botstein D, Lønning PE, Børresen-Dale AL (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98(19):10869–10874PubMedCentralPubMedCrossRef
28.
Weigelt B, Hu Z, He X, Livasy C, Carey LA, Ewend MG, Glas AM, Perou CM, Van’t-Veer LJ (2005) Molecular portraits and 70-gene prognosis signature are preserved throughout the metastatic process of breast cancer. Cancer Res 65(20):9155–9158PubMedCrossRef
29.
Carey LA, Dees EC, Sawyer L, Gatti L, Moore DT, Collichio F, Ollila DW, Sartor CI, Graham ML, Perou CM (2007) The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res 13(8):2329–2334PubMedCrossRef
30.
Sato N, Maehara N, Su GH, Goggins M (2003) Effects of 5-aza-2′-deoxycytidine on matrix metalloproteinase expression and pancreatic cancer cell invasiveness. J Natl Cancer Inst 95(4):327–330PubMedCrossRef
31.
Schneider CA, Rasband WS, Eliceiri KW (2012) Image to ImageJ: 25 years of image analysis. Nat Methods 9(7):671–675PubMedCrossRef
32.
Bos PD, Zhang XH, Nadal C, Shu W, Gomis RR, Nguyen DX, Minn AJ, van de Vijver MJ, Gerald WL, Foekens JA, Massague J (2009) Genes that mediate breast cancer metastasis to the brain. Nature 459(7249):1005–1009PubMedCentralPubMedCrossRef
33.
Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ, Speed D, Lynch AG, Samarajiwa S, Yuan Y, Graf S, Ha G, Haffari G, Bashashati A, Russell R, McKinney S, Langerod A, Green A, Provenzano E, Wishart G, Pinder S, Watson P, Markowetz F, Murphy L, Ellis I, Purushotham A, Borresen-Dale AL, Brenton JD, Tavare S, Caldas C, Aparicio S (2012) The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486(7403):346–352PubMedCentralPubMed
34.
Hatzis C, Pusztai L, Valero V, Booser DJ, Esserman L, Lluch A, Vidaurre T, Holmes F, Souchon E, Wang H, Martin M, Cotrina J, Gomez H, Hubbard R, Chacon JI, Ferrer-Lozano J, Dyer R, Buxton M, Gong Y, Wu Y, Ibrahim N, Andreopoulou E, Ueno NT, Hunt K, Yang W, Nazario A, DeMichele A, O’Shaughnessy J, Hortobagyi GN, Symmans WF (2011) A genomic predictor of response and survival following taxane-anthracycline chemotherapy for invasive breast cancer. JAMA 305(18):1873–1881PubMedCrossRef
35.
Cancer Genome Atlas Network (2012) Comprehensive molecular portraits of human breast tumours. Nature 490(7418):61–70CrossRef
36.
Camp RL, Neumeister V, Rimm DL (2008) A decade of tissue microarrays: progress in the discovery and validation of cancer biomarkers. J Clin Oncol 26(34):5630–5637PubMedCrossRef
37.
Hasegawa M, Furuya M, Kasuya Y, Nishiyama M, Sugiura T, Nikaido T, Momota Y, Ichinose M, Kimura S (2007) CD151 dynamics in carcinoma-stroma interaction: integrin expression, adhesion strength and proteolytic activity. Lab Invest 87(9):882–892PubMedCrossRef
38.
Mitsui H, Suarez-Farinas M, Gulati N, Shah KR, Cannizzaro MV, Coats I, Felsen D, Krueger JG, Carucci JA (2013) Gene Expression Profiling of the Leading Edge of Cutaneous Squamous Cell Carcinoma: IL-24-Driven MMP-7. J Invest Dermatol. doi:10.​1038/​2013.​494
39.
Puthenedam M, Wu F, Shetye A, Michaels A, Rhee KJ, Kwon JH (2011) Matrilysin-1 (MMP7) cleaves galectin-3 and inhibits wound healing in intestinal epithelial cells. Inflamm Bowel Dis 17(1):260–267PubMedCentralPubMedCrossRef
40.
Billar JA, Dueck AC, Stucky CC, Gray RJ, Wasif N, Northfelt DW, McCullough AE, Pockaj BA (2010) Triple-negative breast cancers: unique clinical presentations and outcomes. Ann Surg Oncol 17(Suppl 3):384–390PubMedCrossRef
41.
Kennecke H, Yerushalmi R, Woods R, Cheang MC, Voduc D, Speers CH, Nielsen TO, Gelmon K (2010) Metastatic behavior of breast cancer subtypes. J Clin Oncol 28(20):3271–3277PubMedCrossRef
42.
Charafe-Jauffret E, Ginestier C, Monville F, Finetti P, Adelaide J, Cervera N, Fekairi S, Xerri L, Jacquemier J, Birnbaum D, Bertucci F (2006) Gene expression profiling of breast cell lines identifies potential new basal markers. Oncogene 25(15):2273–2284PubMedCrossRef
43.
Neve RM, Chin K, Fridlyand J, Yeh J, Baehner FL, Fevr T, Clark L, Bayani N, Coppe JP, Tong F, Speed T, Spellman PT, DeVries S, Lapuk A, Wang NJ, Kuo WL, Stilwell JL, Pinkel D, Albertson DG, Waldman FM, McCormick F, Dickson RB, Johnson MD, Lippman M, Ethier S, Gazdar A, Gray JW (2006) A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell 10(6):515–527PubMedCentralPubMedCrossRef
44.
Palmieri D, Bronder JL, Herring JM, Yoneda T, Weil RJ, Stark AM, Kurek R, Vega-Valle E, Feigenbaum L, Halverson D, Vortmeyer AO, Steinberg SM, Aldape K, Steeg PS (2007) Her-2 overexpression increases the metastatic outgrowth of breast cancer cells in the brain. Cancer Res 67(9):4190–4198PubMedCrossRef
45.
Perou CM (2011) Molecular stratification of triple-negative breast cancers. Oncologist 16(Suppl 1):61–70PubMedCrossRef
46.
Prat A, Adamo B, Cheang MC, Anders CK, Carey LA, Perou CM (2013) Molecular characterization of basal-like and non-basal-like triple-negative breast cancer. Oncologist 18(2):123–133PubMedCentralPubMedCrossRef
47.
Prat A, Parker JS, Karginova O, Fan C, Livasy C, Herschkowitz JI, He X, Perou CM (2010) Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res 12(5):R68PubMedCentralPubMedCrossRef
48.
Hu Z, Fan C, Oh DS, Marron JS, He X, Qaqish BF, Livasy C, Carey LA, Reynolds E, Dressler L, Nobel A, Parker J, Ewend MG, Sawyer LR, Wu J, Liu Y, Nanda R, Tretiakova M, Ruiz-Orrico A, Dreher D, Palazzo JP, Perreard L, Nelson E, Mone M, Hansen H, Mullins M, Quackenbush JF, Ellis MJ, Olopade OI, Bernard PS, Perou CM (2006) The molecular portraits of breast tumors are conserved across microarray platforms. BMC Genom 7:96CrossRef
49.
Crawford HC, Fingleton BM, Rudolph-Owen LA, Goss KJ, Rubinfeld B, Polakis P, Matrisian LM (1999) The metalloproteinase matrilysin is a target of beta-catenin transactivation in intestinal tumors. Oncogene 18(18):2883–2891PubMedCrossRef
50.
Brenton JD, Carey LA, Ahmed AA, Caldas C (2005) Molecular classification and molecular forecasting of breast cancer: ready for clinical application? J Clin Oncol 23(29):7350–7360PubMedCrossRef
51.
Cakir A, Gonul II, Uluoglu O (2012) A comprehensive morphological study for basal-like breast carcinomas with comparison to nonbasal-like carcinomas. Diagn Pathol 7:145PubMedCentralPubMedCrossRef
52.
Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, Hernandez-Boussard T, Livasy C, Cowan D, Dressler L, Akslen LA, Ragaz J, Gown AM, Gilks CB, van de Rijn M, Perou CM (2004) Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 10(16):5367–5374PubMedCrossRef
53.
Rodriguez-Pinilla SM, Sarrio D, Honrado E, Moreno-Bueno G, Hardisson D, Calero F, Benitez J, Palacios J (2007) Vimentin and laminin expression is associated with basal-like phenotype in both sporadic and BRCA1-associated breast carcinomas. J Clin Pathol 60(9):1006–1012PubMedCentralPubMedCrossRef
54.
Sousa B, Paredes J, Milanezi F, Lopes N, Martins D, Dufloth R, Vieira D, Albergaria A, Veronese L, Carneiro V, Carvalho S, Costa JL, Zeferino L, Schmitt F (2010) P-cadherin, vimentin and CK14 for identification of basal-like phenotype in breast carcinomas: an immunohistochemical study. Histol Histopathol 25(8):963–974PubMed
55.
Balak MN, Gong Y, Riely GJ, Somwar R, Li AR, Zakowski MF, Chiang A, Yang G, Ouerfelli O, Kris MG, Ladanyi M, Miller VA, Pao W (2006) Novel D761Y and common secondary T790 M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clin Cancer Res 12(21):6494–6501PubMedCrossRef
56.
Suda K, Onozato R, Yatabe Y, Mitsudomi T (2009) EGFR T790 M mutation: a double role in lung cancer cell survival? J Thorac Oncol 4(1):1–4PubMedCrossRef
57.
Zucker S, Cao J, Chen WT (2000) Critical appraisal of the use of matrix metalloproteinase inhibitors in cancer treatment. Oncogene 19(56):6642–6650PubMedCrossRef
58.
Zheng G, Chen J, Stefflova K, Jarvi M, Li H, Wilson BC (2007) Photodynamic molecular beacon as an activatable photosensitizer based on protease-controlled singlet oxygen quenching and activation. PNAS 104(21):8989–8994PubMedCentralPubMedCrossRef
59.
Liu S, Netzel-Arnett S, Birkedal-Hansen H, Leppla SH (2000) Tumor cell-selective cytotoxicity of matrix metalloproteinase-activated anthrax toxin. Cancer Res 60(21):6061–6067PubMed
60.
Liu S, Wang H, Currie BM, Molinolo A, Leung HJ, Moayeri M, Basile JR, Alfano RW, Gutkind JS, Frankel AE, Bugge TH, Leppla SH (2008) Matrix metalloproteinase-activated anthrax lethal toxin demonstrates high potency in targeting tumor vasculature. J Biol Chem 283(1):529–540PubMedCentralPubMedCrossRef
Metadata
Title
Hypomethylation of the MMP7 promoter and increased expression of MMP7 distinguishes the basal-like breast cancer subtype from other triple-negative tumors
Authors
Steven T. Sizemore
Gina M. Sizemore
Christine N. Booth
Cheryl L. Thompson
Paula Silverman
Gurkan Bebek
Fadi W. Abdul-Karim
Stefanie Avril
Ruth A. Keri
Publication date
01-07-2014
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 1/2014
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-014-2989-4

Other articles of this Issue 1/2014

Breast Cancer Research and Treatment 1/2014 Go to the issue

Review

Breast cancer and aging: results of the U13 conference breast cancer panel

Brief Report

Somatic mutation load of estrogen receptor-positive breast tumors predicts overall survival: an analysis of genome sequence data

Clinical Trial

A prospective assessment of musculoskeletal toxicity and loss of grip strength in breast cancer patients receiving adjuvant aromatase inhibitors and tamoxifen, and relation with BMI

Clinical Trial

Quality of life and patient satisfaction after microsurgical abdominal flap versus staged expander/implant breast reconstruction: a critical study of unilateral immediate breast reconstruction using patient-reported outcomes instrument BREAST-Q

Letter to the Editor

Sentinel lymph node identification rates and axillary concordance can only be accurately determined by comparing ‘like with like’ injected materials

Epidemiology

Outcome of triple negative breast cancer: comparison of sporadic and BRCA1-associated cancers
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits