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 STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2019

Open Access 01-12-2019 | Breast Cancer | Research article

Pathway activity profiling of growth factor receptor network and stemness pathways differentiates metaplastic breast cancer histological subtypes

Authors: Jasmine A. McQuerry, David F. Jenkins, Susan E. Yost, Yuqing Zhang, Daniel Schmolze, W. Evan Johnson, Yuan Yuan, Andrea H. Bild

Published in: BMC Cancer | Issue 1/2019

Login to get access

Abstract

Background

Gene expression profiling of rare cancers has proven challenging due to limited access to patient materials and requirement of intact, non-degraded RNA for next-generation sequencing. We customized a gene expression panel compatible with degraded RNA from formalin-fixed, paraffin-embedded (FFPE) patient cancer samples and investigated its utility in pathway activity profiling in patients with metaplastic breast cancer (MpBC).

Methods

Activity of various biological pathways was profiled in samples from nineteen patients with MpBC and 8 patients with invasive ductal carcinoma with triple negative breast cancer (TNBC) phenotype using a custom gene expression-based assay of 345 genes.

Results

MpBC samples of mesenchymal (chondroid and/or osteoid) histology demonstrated increased SNAI1 and BCL2L11 pathway activity compared to samples with non-mesenchymal histology. Additionally, late cornified envelope and keratinization genes were downregulated in MpBC compared to TNBC, and epithelial-to-mesenchymal transition (EMT) and collagen genes were upregulated in MpBC. Patients with high activity of an invasiveness gene expression signature, as well as high expression of the mesenchymal marker and extracellular matrix glycoprotein gene SPARC, experienced worse outcomes than those with low invasiveness activity and low SPARC expression.

Conclusions

This study demonstrates the utility of gene expression profiling of metaplastic breast cancer FFPE samples with a custom counts-based assay. Gene expression patterns identified by this assay suggest that, although often histologically triple negative, patients with MpBC have distinct pathway activation compared to patients with invasive ductal TNBC. Incorporation of targeted therapies may lead to improved outcome for MpBC patients, especially in those patients expressing increased activity of invasiveness pathways.
Appendix
Available only for authorised users
Literature
1.
McKinnon E, Xiao P. Metaplastic carcinoma of the breast. Arch Pathol Lab Med. 2015;139(6):819–22.PubMedCrossRef
2.
El Zein D, Hughes M, Kumar S, Peng X, Oyasiji T, Jabbour H, Khoury T. Metaplastic carcinoma of the breast is more aggressive than triple negative breast cancer: A study from a single institution and review of literature. Clin Breast Cancer. 2017;17(5):382–91.PubMedPubMedCentralCrossRef
3.
Mills MN, Yang GQ, Oliver DE, Liveringhouse CL, Ahmed KA, Orman AG, Laronga C, Hoover SJ, Khakpour N, Costa RLB, et al. Histologic heterogeneity of triple negative breast cancer: a National Cancer Center database analysis. Eur J Cancer. 2018;98:48–58.PubMedCrossRef
4.
Jung S, Kim HY, Nam B, Min SY, Lee SJ, Park C, Kwon Y, Kim E, KL KO, Shin KH, et al. Worse prognosis of metaplastic breast cancer patients than other patients with triple-negative breast cancer. Breast Cancer Res Treat. 2010;120(3):627–37.PubMedCrossRef
5.
Chen IC, Lin CH, Huang CS, Lien HC, Hsu C, Kuo WH, Lu YS, Cheng AL. Lack of efficacy to systemic chemotherapy for treatment of metaplastic carcinoma of the breast in the modern era. Breast Cancer Res Treat. 2011;130:345–51.PubMedCrossRef
6.
Piscuoglio S, Ng CKY, Geyer FC, Burke KA, Cowell CF, Martelotto LG, Natrajan R, Popova T, Maher CA, Lim RS, et al. Genomic and transcriptomic heterogeneity in metaplastic carcinomas of the breast. NPJ Breast Cancer. 2017;3:48.PubMedPubMedCentralCrossRef
7.
Krings G, Chen Y. Genomic profiling of metaplastic breast carcinomas reveals genetic heterogeneity and relationship to ductal carcinoma. Mod Pathol. 2018;31(11):1661–74.PubMedCrossRef
8.
Norton N, Sun Z, Asmann YW, Serie DJ, Necela BM, Bhagwate A, Jen J, Eckloff BW, Kalari KR, Thompson KJ, et al. Gene expression, single nucleotide variant and fusion transcript discovery in archival material from breast tumors. PLoS One. 2013;8(11):e81925.PubMedPubMedCentralCrossRef
9.
Stricker TP, Morales La Madrid a, Chlenski a, Guerrero L, Salwen HR, Gosiengfiao Y, Perlman EJ, Furman W, Bahrami a, Shohet JM, et al. validation of a prognostic multi-gene signature in high-risk neuroblastoma using the high throughput digital NanoString nCounterTM system. Mol Oncol. 2014;8(3):669–78.PubMedPubMedCentralCrossRef
10.
Veldman-Jones MH, Brant R, Rooney C, Geh C, Emery H, Harbron CG, Wappett M, Sharpe A, Dymond M, Barrett JC, et al. Evaluating robustness and sensitivity of the NanoString technologies nCounter platform to enable multiplexed gene expression analysis of clinical samples. Cancer Res. 2015;75(13):2587–93.PubMedCrossRef
11.
Lakhani SR, Ellis IO, Schnitt SJ, Tan PH, van de Vijver MJ. WHO classification of tumors of the breast. 4th ed. Lyon: IARC Press; 2012.
12.
Rahman M, MacNeil SM, Jenkins DF, Shrestha G, Wyatt SR, McQuerry JA, Piccolo SR, Heiser LM, Gray JW, Johnson WE, et al. Activity of distinct growth factor receptor network components in breast tumors uncovers two biologically relevant subtypes. Genome Med. 2017;9(1):40.PubMedPubMedCentralCrossRef
13.
Anastassiou D, Rumjantseva V, Cheng W, Huang J, Canoll PD, Yamashiro DJ, Kandel JJ. Human cancer cells express slug-based epithelial-mesenchymal transition gene expression signature obtained in vivo. BMC Cancer. 2011;11:529.PubMedPubMedCentralCrossRef
14.
Boquest AC, Shahdadfar A, Frønsdal K, Sigurjonsson O, Tunheim SH, Collas P, Brinchmann JE. Isolation and transcription profiling of purified uncultured human stromal stem cells: alteration of gene expression after in vitro cell culture. Mol Biol Cell. 2005;16(3):1131–41.PubMedPubMedCentralCrossRef
15.
Phong MS, Van Horn RD, Li S, Tucker-Kellogg G, Surana U, Ye XS. p38 mitogen-activated protein kinase promotes cell survival in response to DNA damage but is not required for the G(2) DNA damage checkpoint in human cancer cells. Mol Cell Biol. 2010;30(15):3816–26.PubMedPubMedCentralCrossRef
16.
Shen Y, Rahman M, Piccolo SR, Gusenleitner D, El-Chaar NN, Cheng L, Monti S, Bild AH, Johnson WE. ASSIGN: context-specific genomic profiling of multiple heterogeneous pathways. Bioinformatics. 2015;31(11):1745–53.PubMedPubMedCentralCrossRef
17.
Tse C, Shoemaker AR, Adickes J, Anderson MG, Chen J, Jin S, Johnson EF, Marsh KC, Mitten MJ, Nimmer P, Roberts L. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 2008;68(9):3421–8.PubMedCrossRef
18.
Taube JH, Herschkowitz JI, Komurov K, Zhou AY, Gupta S, Yang J, Hartwell K, Onder TT, Gupta PB, Evans KW, et al. Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes. P Natl Acad Sci USA. 2010;107(35):15449–54.CrossRef
19.
Brady SW, McQuerry JA, Qiao Y, Piccolo SR, Shrestha G, Jenkins DF, Layer RM, Pedersen BS, Miller RH, Esch A, et al. Combating subclonal evolution of resistant cancer phenotypes. Nat Commun. 2017;8:1231.PubMedPubMedCentralCrossRef
20.
Geiss GK, Bumgarner RE, Birditt B, Dahl T, Dowidar N, Dunaway DL, Fell HP, Ferree S, George RD, Grogan T, et al. Direct multiplexed measurement of gene expression with color-coded probe pairs. Nat Biotechnol. 2008;26:317–25.PubMedCrossRef
21.
Wang H, Horbinski C, Wu H, Liu Y, Sheng S, Liu J, Weiss H, Stromberg AJ, Wang C. NanoStringDiff: a novel statistical method for differential expression analysis based on NanoString nCounter data. Nucleic Acids Res. 2016;44(20):e151.PubMedPubMedCentralCrossRef
22.
Lien HC, Hsiao YH, Lin YS, Yao YT, Juan HF, Kuo WH, Hung MC, Chang KJ, Hsieh FJ. Molecular signatures of metaplastic carcinoma of the breast by large-scale transcriptional profiling: identification of genes potentially related to epithelial-mesenchymal transition. Oncogene. 2007;26(57):7859–71.PubMedCrossRef
23.
Oon ML, Thike AA, Tan SY, Tan PH. Cancer stem cell and epithelial-mesenchymal transition markers predict worse outcome in metaplastic carcinoma of the breast. Breast Cancer Res Treat. 2015;150:31–41.PubMedCrossRef
24.
Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A. 2003;100(7):3983–8.PubMedPubMedCentralCrossRef
25.
Liu S, Cong Y, Wang D, Sun Y, Deng L, Liu Y, Martin-Trevino R, Shang L, McDermott SP, Landis MD, et al. Breast cancer stem cells transition between epithelial and mesenchymal states reflective of their normal counterparts. Stem Cell Rep. 2014;2(1):78–91.CrossRef
26.
Desai A, Yan Y, Gerson SL. Concise reviews: Cancer stem cell targeted therapies: toward clinical success. Stem Cells Transl Med. 2019;8(1):75–81.PubMedCrossRef
27.
Kusafuka K, Muramatsu K, Kasami M, Kuriki K, Hirobe K, Hayashi I, Watanabe H, Hiraki Y, Shukunami C, Mochizuki T, et al. Cartilagenous features in matrix-producing carcinoma of the breast: four cases report with histochemical and immunohistochemical analysis of matrix molecules. Mod Pathol. 2008;21:1282–92.PubMedCrossRef
28.
Liu J, Shen JX, Wu HT, Li XL, Wen XF, Du CW, Zhang GJ. Collagen 1A1 (COL1A1) promotes metastasis of breast cancer and is a potential therapeutic target. Discov Med. 2018;25(139):211–23.PubMed
29.
Phillips L, Gill AJ, Baxter RC. Novel prognostic markers in triple-negative breast cancer discovered by MALDI-mass spectrometry imaging. Front Oncol. 2019;9:379.PubMedPubMedCentralCrossRef
30.
Lien HC, Lee YH, Jeng YM, Lin CH, Lu YS, Yao YT. Differential expression of hyaluronan synthase 2 in breast carcinoma and its biological significance. Histopathology. 2014;65(3):328–39.PubMedCrossRef
31.
Doherty GJ, Tempero M, Corrie PG. HALO-109-301: a phase III trial of PEGPH20 (with gemcitabine and nab-paclitaxel) in hyaluronic acid-high stage IV pancreatic cancer. Future Oncol. 2018;14(1):13–22.PubMedCrossRef
32.
ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Study of Eribulin Mesylate in Combination With PEGylated Recombinant Human Hyaluronidase (PEGPH20) Versus Eribulin Mesylate Alone in Subjects With Human Epidermal Growth Factor Receptor 2 (HER2)-Negative, High-Hyaluronan (HA) Metastatic Breast Cancer (MBC); 2016. Available from: https://​clinicaltrials.​gov/​ct2/​show/​NCT02753595. Apr 28 [cited 2019 Jul 12]; [about 3 screens]. 2000 Feb 29 -present. Identifier NCT02753595
33.
ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). A Study of Subcutaneous Nivolumab Monotherapy With or Without Recombinant Human Hyaluronidase PH20 (rHuPH20); 2018 Sept. Available from: https://​clinicaltrials.​gov/​ct2/​show/​NCT03656718. 3 [cited 2019 Jul 12]; [about 3 screens]2000 Feb 29 –present, Identifier NCT03656718
34.
Gwin K, Buell-Gutbrod R, Tretiakova M, Montag A. Epithelial-to-mesenchymal transition in metaplastic breast carcinomas with chondroid differentiation: expression of the E-cadherin repressor snail. Appl Immunohistochem Mol Morphol. 2010;18(6):526–31.PubMedCrossRef
35.
Lee SH, Shen GN, Jung YS, Lee SJ, Chung JY, Kim HS, Xu Y, Choi Y, Lee JW, Ha NC, et al. Antitumor effect of novel small chemical inhibitors of snail-p53 binding in K-Ras mutated cancer cells. Oncogene. 2010;29(32):4576–87.PubMedCrossRef
36.
Javaid S, Zhang J, Anderssen E, Black JC, Wittner BS, Tajima K, Ting DT, Smolen GA, Zubrowski M, Desai R, et al. Dynamic chromatin modification sustains epithelial-mesenchymal transition following inducible expression of Snail-1. Cell Rep. 2013;5(6):1679–89.PubMedPubMedCentralCrossRef
37.
Shah P, Gau Y, Sabnis G. Histone deacetylase inhibitor entinostat reverses epithelial to mesenchymal transition of breast cancer cells by reversing the expression of E-cadherin. Breast Cancer Res Treat. 2014;143(1):99–111.PubMedCrossRef
38.
Merino D, Best SA, Asselin-Labat M-L, Vaillant F, Pal B, Dickins RA, Anderson RL, Bouillet P, Lindeman GJ, Visvader JE. Pro-apoptotic Bim suppresses breast tumor cell metastasis and is a target gene of SNAI2. Oncogene. 2015;34:3926–34.PubMedCrossRef
39.
Szynglarewicz B, Kasprzak P, Donizy P, Biecek P, Halon A, Matkowski R. Ductal carcinoma in situ on stereotactic biopsy of suspicious breast microcalcifications: expression of SPARC (secreted protein, acidic and rich in cysteine) can predict postoperative invasion. J Surg Oncol. 2016;114:548–56.PubMedCrossRef
40.
Zhu A, Yuan P, Du F, Hong R, Ding X, Shi X, Fan Y, Wang J, Luo Y, Ma F. SPARC overexpression in primary tumors correlates with disease recurrence and overall survival in patients with triple negative breast cancer. Oncotarget. 2016;7(47):76628–34.PubMedPubMedCentralCrossRef
41.
Hennessy BT, Giordano S, Broglio K, Duan Z, Trent J, Buchholz TA, Babiera G, Hortobagyi GN, Valero V. Biphasic metaplastic sarcomatoid carcinoma of the breast. Ann Oncol. 2006;17(4):605–13.PubMedCrossRef
42.
Yam C, Hess KR, Litton JK, Yang WT, Piwnica-Worms H, Mittendorf EA, Ueno NT, Lim B, Murthy RK, Damodaran SK. A randomized, triple negative breast cancer enrolling trial to confirm molecular profiling improves survival (ARTEMIS). Proceedings of the 2017 ASCO annual meeting. J Clin Oncol. 2017;35(15):TPS590.CrossRef
43.
Nanda R, Liu MC, Yau C, Asare S, Hylton N, Van’t Veer L, Perlmutter J, Wallace AM, Chien AJ, Forero-Torres A, et al. Pembrolizumab plus standard neoadjuvant therapy for high-risk breast cancer (BC): Results from I-SPY2. J Clin Oncol. 2017;35(15):506.CrossRef
44.
Moulder SL, Hess KR, Candelaria RP, Rauch GM, Santiago L, Adrada B, Yang WT, Gilcrease MZ, Huo L, Stauder MC, et al. Precision neoadjuvant therapy (P-NAT): A planned interim analysis of a randomized, TNBC enrolling trial to confirm molecular profiling improves survival (ARTEMIS). Proceedings of the 2018 annual ASCO meeting. J Clin Oncol. 2018;36(15):518.CrossRef
Metadata
Title
Pathway activity profiling of growth factor receptor network and stemness pathways differentiates metaplastic breast cancer histological subtypes
Authors
Jasmine A. McQuerry
David F. Jenkins
Susan E. Yost
Yuqing Zhang
Daniel Schmolze
W. Evan Johnson
Yuan Yuan
Andrea H. Bild
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2019
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-019-6052-z

Other articles of this Issue 1/2019

BMC Cancer 1/2019 Go to the issue

Research article

Overexpression of Pin1 and rho signaling partners correlates with metastatic behavior and poor recurrence-free survival of hepatocellular carcinoma patients

Research article

Dynamic and unpredictable changes in mutant allele fractions of BRAF and NRAS during visceral progression of cutaneous malignant melanoma

Research article

Identification of non-invasive biomarkers for chronic atrophic gastritis from serum exosomal microRNAs

Research article

miR-196a-5p promotes metastasis of colorectal cancer via targeting IκBα

Research article

Less micrometastatic risk related to circulating tumor cells after endoscopic breast cancer surgery compared to open surgery

Research article

Genetic associations between the miRNA polymorphisms miR-130b (rs373001), miR-200b (rs7549819), and miR-495 (rs2281611) and colorectal cancer susceptibility
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