Bone marrow stromal antigen 2 expressed in cancer cells promotes mammary tumor growth and metastasis

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Abstract

Introduction

Several innate immunity genes are overexpressed in human cancers and their roles remain controversial. Bone marrow stromal antigen 2 (BST-2) is one such gene whose role in cancer is not clear. BST-2 is a unique innate immunity gene with both antiviral and pro-tumor functions and therefore can serve as a paradigm for understanding the roles of other innate immunity genes in cancers.

Methods

Meta-analysis of tumors from breast cancer patients obtained from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets were evaluated for levels of BST-2 expression and for tumor aggressiveness. In vivo, we examined the effect of knockdown of BST-2 in two different murine carcinoma cells on tumor growth, metastasis, and survival . In vitro, we assessed the effect of carcinoma cell BST-2 knockdown and/or overexpression on adhesion, anchorage-independent growth, migration, and invasion.

Results

BST-2 in breast tumors and mammary cancer cells is a strong predictor of tumor size, tumor aggressiveness, and host survival. In humans, BST-2 mRNA is elevated in metastatic and invasive breast tumors. In mice, orthotopic implantation of mammary tumor cells lacking BST-2 increased tumor latency, decreased primary tumor growth, reduced metastases to distal organs, and prolonged host survival. Furthermore, we found that the cellular basis for the role of BST-2 in promoting tumorigenesis include BST-2-directed enhancement in cancer cell adhesion, anchorage-independency, migration, and invasion.

Conclusions

BST-2 contributes to the emergence of neoplasia and malignant progression of breast cancer. Thus, BST-2 may (1) serve as a biomarker for aggressive breast cancers, and (2) be a novel target for breast cancer therapeutics.

Electronic supplementary material

The online version of this article (doi:10.1186/s13058-014-0493-8) contains supplementary material, which is available to authorized users.

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Most cited references 44

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Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu.

Stuart J D Neil, Trinity Zang, Paul D. Bieniasz (2008)

Human cells possess an antiviral activity that inhibits the release of retrovirus particles, and other enveloped virus particles, and is antagonized by the HIV-1 accessory protein, Vpu. This antiviral activity can be constitutively expressed or induced by interferon-alpha, and it consists of protein-based tethers, which we term 'tetherins', that cause retention of fully formed virions on infected cell surfaces. Using deductive constraints and gene expression analyses, we identify CD317 (also called BST2 or HM1.24), a membrane protein of previously unknown function, as a tetherin. Specifically, CD317 expression correlated with, and induced, a requirement for Vpu during HIV-1 and murine leukaemia virus particle release. Furthermore, in cells where HIV-1 virion release requires Vpu expression, depletion of CD317 abolished this requirement. CD317 caused retention of virions on cell surfaces and, after endocytosis, in CD317-positive compartments. Vpu co-localized with CD317 and inhibited these effects. Inhibition of Vpu function and consequent mobilization of tetherin's antiviral activity is a potential therapeutic strategy in HIV/AIDS.

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Genetic reclassification of histologic grade delineates new clinical subtypes of breast cancer.

Anna Ivshina, Joshy George, Oleg Senko … (2006)

Histologic grading of breast cancer defines morphologic subtypes informative of metastatic potential, although not without considerable interobserver disagreement and clinical heterogeneity particularly among the moderately differentiated grade 2 (G2) tumors. We posited that a gene expression signature capable of discerning tumors of grade 1 (G1) and grade 3 (G3) histology might provide a more objective measure of grade with prognostic benefit for patients with G2 disease. To this end, we studied the expression profiles of 347 primary invasive breast tumors analyzed on Affymetrix microarrays. Using class prediction algorithms, we identified 264 robust grade-associated markers, six of which could accurately classify G1 and G3 tumors, and separate G2 tumors into two highly discriminant classes (termed G2a and G2b genetic grades) with patient survival outcomes highly similar to those with G1 and G3 histology, respectively. Statistical analysis of conventional clinical variables further distinguished G2a and G2b subtypes from each other, but also from histologic G1 and G3 tumors. In multivariate analyses, genetic grade was consistently found to be an independent prognostic indicator of disease recurrence comparable with that of lymph node status and tumor size. When incorporated into the Nottingham prognostic index, genetic grade enhanced detection of patients with less harmful tumors, likely to benefit little from adjuvant therapy. Our findings show that a genetic grade signature can improve prognosis and therapeutic planning for breast cancer patients, and support the view that low- and high-grade disease, as defined genetically, reflect independent pathobiological entities rather than a continuum of cancer progression.

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Estimation of rat mammary tumor volume using caliper and ultrasonography measurements.

Ana Isabel Faustino-Rocha, Paula A. Oliveira, Jacinta Pinho-Oliveira … (2013)

Mammary tumors similar to those observed in women can be induced in rats by intraperitoneal administration of N-methyl-N-nitrosourea. Determining tumor volume is a useful and quantitative way to monitor tumor progression. In this study, the authors measured dimensions of rat mammary tumors using a caliper and using real-time compound B-mode ultrasonography. They then used different formulas to calculate tumor volume from these tumor measurements and compared the calculated tumor volumes with the real tumor volume to identify the formulas that gave the most accurate volume calculations. They found that caliper and ultrasonography measurements were significantly correlated but that tumor volumes calculated using different formulas varied substantially. Mammary tumors seemed to take on an oblate spheroid geometry. The most accurate volume calculations were obtained using the formula V = (W(2) × L)/2 for caliper measurements and the formula V = (4/3) × π × (L/2) × (L/2) × (D/2) for ultrasonography measurements, where V is tumor volume, W is tumor width, L is tumor length and D is tumor depth.

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Author and article information

Contributors

Wadie D Mahauad-Fernandez: wadiedaniel-mahauadfernandez@uiowa.edu

Kris A DeMali: kris-demali@uiowa.edu

Alicia K Olivier: aolivier@cvm.msstate.edu

Chioma M Okeoma: chioma-okeoma@uiowa.edu

Journal

Journal ID (nlm-ta): Breast Cancer Res

Title: Breast Cancer Research : BCR

Publisher: BioMed Central (London )

ISSN (Print): 1465-5411

ISSN (Electronic): 1465-542X

Publication date (Electronic): 13 December 2014

Publication date PMC-release: 13 December 2014

Publication date (Print): 2014

Volume: 16

Issue: 6

Electronic Location Identifier: 493

Affiliations

[ ]Department of Microbiology, Carver College of Medicine, University of Iowa, 51 Newton Road, Iowa City, IA 52242-1109 USA

[ ]Interdisciplinary Graduate Program in Molecular and Cellular Biology (MCB), University of Iowa, 500 Newton Road, Iowa City, IA 52242-1109 USA

[ ]Department of Biochemistry, Carver College of Medicine, University of Iowa, 51 Newton Road, Iowa City, IA 52242-1109 USA

[ ]Department of Pathology, Carver College of Medicine, University of Iowa, 51 Newton Road, Iowa City, IA 52242-1109 USA

[ ]Department of Pathobiology and Population Medicine, College of Veterinary Medicine, Mississippi State University, 240 Wise Center Drive, Starkville, MS 39762-6100 USA

Article

Publisher ID: 493

DOI: 10.1186/s13058-014-0493-8

PMC ID: 4308845

PubMed ID: 25499888

SO-VID: eb320c05-abb9-4873-b55c-4580a4d0d268

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 24 July 2014

Date accepted : 2 December 2014

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ScienceOpen disciplines: Oncology & Radiotherapy

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ScienceOpen disciplines: Oncology & Radiotherapy

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Bone marrow stromal antigen 2 expressed in cancer cells promotes mammary tumor growth and metastasis

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Abstract

Introduction

Methods

Results

Conclusions

Electronic supplementary material

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Karger: Oncology

Most cited references 44

Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu.

Genetic reclassification of histologic grade delineates new clinical subtypes of breast cancer.

Estimation of rat mammary tumor volume using caliper and ultrasonography measurements.

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Cited by 34

Most referenced authors 742