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 2023 EHA Congress 2023 ASCO Annual Meeting
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
Published in: Breast Cancer Research 1/2016

Open Access 01-12-2016 | Research article

SMARCE1 regulates metastatic potential of breast cancer cells through the HIF1A/PTK2 pathway

Authors: Aarti Sethuraman, Martin Brown, Tiffany N. Seagroves, Zhao-Hui Wu, Lawrence M. Pfeffer, Meiyun Fan

Published in: Breast Cancer Research | Issue 1/2016

Login to get access

Abstract

Background

While aberrant activation of the chromatin-remodeling SWI/SNF complexes has been associated with cancer development and progression, the role of each subunit in tumor cells is poorly defined. This study is aimed to characterize the role of SMARCE1/BAF57 in regulating metastasis of breast cancer cells.

Methods

Genetic approaches and chemical inhibitors were used to manipulate the activities of SMARCE1 and its downstream targets in multiple breast cancer cell lines. Xenograft mouse models were used to analyze the role of SMARCE1 in lung metastasis in vivo. Nonadherent culture conditions were used to elucidate the role of SMARCE1 in regulating anoikis. Chromatin immunoprecipitation (ChIP), immunoprecipitation, and immunoblotting assays were designed to dissect the mechanism of action of SMARCE1. Public databases were used to investigate the relationship between SMARCE1 deregulation and breast cancer prognosis.

Results

SMARCE1 knockdown reduced lung metastasis of breast cancer cells and sensitized tumor cells to anoikis. In response to loss of attachment, SMARCE1 interacted with and potentiated transcriptional activity of HIF1A, resulting in rapid PTK2 activation. Both HIF1A and PTK2 were indispensable for SMARCE1-mediated protection against anoikis by promoting activation of ERK and AKT pathways while suppressing the expression of pro-apoptotic BIM protein. Expression data analysis of a large cohort of human breast tumors revealed that high expression of SMARCE1 or PTK2 is associated with poor prognosis and tumor relapse, and PTK2 expression is positively correlated with SMARCE1 expression in basal-like and luminal B subtypes of breast tumors.

Conclusions

SMARCE1 plays an essential role in breast cancer metastasis by protecting cells against anoikis through the HIF1A/PTK2 pathway. SMARCE1-mediated PTK2 activation likely plays a key role in promoting metastasis of basal-like and luminal B subtype of breast tumors.
Literature
1.
2.
3.
4.
Labelle M, Hynes RO. The initial hours of metastasis: the importance of cooperative host-tumor cell interactions during hematogenous dissemination. Cancer Discov. 2012;2(12):1091–9.CrossRefPubMedPubMedCentral
5.
6.
Kadoch C, Hargreaves DC, Hodges C, Elias L, Ho L, Ranish J, Crabtree GR. Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy. Nat Genet. 2013;45(6):592–601.CrossRefPubMedPubMedCentral
7.
Kiskinis E, Garcia-Pedrero JM, Villaronga MA, Parker MG, Belandia B. Identification of BAF57 mutations in human breast cancer cell lines. Breast Cancer Res Treat. 2006;98(2):191–8.CrossRefPubMed
8.
Wilson BG, Helming KC, Wang X, Kim Y, Vazquez F, Jagani Z, Hahn WC, Roberts CW. Residual complexes containing SMARCA2 (BRM) underlie the oncogenic drive of SMARCA4 (BRG1) mutation. Mol Cell Biol. 2014;34(6):1136–44.CrossRefPubMedPubMedCentral
9.
Oike T, Ogiwara H, Tominaga Y, Ito K, Ando O, Tsuta K, Mizukami T, Shimada Y, Isomura H, Komachi M, et al. A synthetic lethality-based strategy to treat cancers harboring a genetic deficiency in the chromatin remodeling factor BRG1. Cancer Res. 2013;73(17):5508–18.CrossRefPubMed
10.
11.
12.
Davis LM, Harris C, Tang L, Doherty P, Hraber P, Sakai Y, Bocklage T, Doeden K, Hall B, Alsobrook J, et al. Amplification patterns of three genomic regions predict distant recurrence in breast carcinoma. J Mol Diagn. 2007;9(3):327–36.CrossRefPubMedPubMedCentral
13.
Krutilina R, Sun W, Sethuraman A, Brown M, Seagroves TN, Pfeffer LM, Ignatova T, Fan M. MicroRNA-18a inhibits hypoxia-inducible factor 1alpha activity and lung metastasis in basal breast cancers. Breast Cancer Res. 2014;16(4):R78.CrossRefPubMedPubMedCentral
14.
Fan M, Krutilina R, Sun J, Sethuraman A, Yang CH, Wu ZH, Yue J, Pfeffer LM. Comprehensive analysis of microRNA (miRNA) targets in breast cancer cells. J Biol Chem. 2013;288(38):27480–93.CrossRefPubMedPubMedCentral
15.
Patsialou A, Wang Y, Lin J, Whitney K, Goswami S, Kenny PA, Condeelis JS. Selective gene-expression profiling of migratory tumor cells in vivo predicts clinical outcome in breast cancer patients. Breast Cancer Res. 2012;14(5):R139.CrossRefPubMedPubMedCentral
16.
17.
Garcia-Pedrero JM, Kiskinis E, Parker MG, Belandia B. The SWI/SNF chromatin remodeling subunit BAF57 is a critical regulator of estrogen receptor function in breast cancer cells. J Biol Chem. 2006;281(32):22656–64.CrossRefPubMed
18.
Paoli P, Giannoni E, Chiarugi P. Anoikis molecular pathways and its role in cancer progression. Biochim Biophys Acta. 2013;1833(12):3481–98.CrossRefPubMed
19.
Guadamillas MC, Cerezo A, Del Pozo MA. Overcoming anoikis--pathways to anchorage-independent growth in cancer. J Cell Sci. 2011;124(Pt 19):3189–97.CrossRefPubMed
20.
Zouq NK, Keeble JA, Lindsay J, Valentijn AJ, Zhang L, Mills D, Turner CE, Streuli CH, Gilmore AP. FAK engages multiple pathways to maintain survival of fibroblasts and epithelia: differential roles for paxillin and p130Cas. J Cell Sci. 2009;122(Pt 3):357–67.CrossRefPubMedPubMedCentral
21.
Kallergi G, Markomanolaki H, Giannoukaraki V, Papadaki MA, Strati A, Lianidou ES, Georgoulias V, Mavroudis D, Agelaki S. Hypoxia-inducible factor-1alpha and vascular endothelial growth factor expression in circulating tumor cells of breast cancer patients. Breast Cancer Res. 2009;11(6):R84.CrossRefPubMedPubMedCentral
22.
Consortium EP. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;489(7414):57–74.CrossRef
23.
Whelan KA, Schwab LP, Karakashev SV, Franchetti L, Johannes GJ, Seagroves TN, Reginato MJ. The oncogene HER2/neu (ERBB2) requires the hypoxia-inducible factor HIF-1 for mammary tumor growth and anoikis resistance. J Biol Chem. 2013;288(22):15865–77.CrossRefPubMedPubMedCentral
24.
Sena JA, Wang L, Hu CJ. BRG1 and BRM chromatin-remodeling complexes regulate the hypoxia response by acting as coactivators for a subset of hypoxia-inducible transcription factor target genes. Mol Cell Biol. 2013;33(19):3849–63.CrossRefPubMedPubMedCentral
25.
Kenneth NS, Mudie S, van Uden P, Rocha S. SWI/SNF regulates the cellular response to hypoxia. J Biol Chem. 2009;284(7):4123–31.CrossRefPubMed
26.
Stampfer MR, Bartley JC. Induction of transformation and continuous cell lines from normal human mammary epithelial cells after exposure to benzo[a]pyrene. Proc Natl Acad Sci U S A. 1985;82(8):2394–8.CrossRefPubMedPubMedCentral
27.
Gyorffy B, Lanczky A, Eklund AC, Denkert C, Budczies J, Li Q, Szallasi Z. An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients. Breast Cancer Res Treat. 2010;123(3):725–31.CrossRefPubMed
28.
Cancer Genome Atlas N. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61–70.CrossRef
29.
Wilson BG, Roberts CW. SWI/SNF nucleosome remodellers and cancer. Nat Rev Cancer. 2011;11(7):481–92.CrossRefPubMed
30.
Kadoch C, Crabtree GR. Mammalian SWI/SNF chromatin remodeling complexes and cancer: Mechanistic insights gained from human genomics. Sci Adv. 2015;1(5):e1500447.CrossRefPubMedPubMedCentral
31.
Frisch SM, Francis H. Disruption of epithelial cell-matrix interactions induces apoptosis. J Cell Biol. 1994;124(4):619–26.CrossRefPubMed
32.
Mailleux AA, Overholtzer M, Brugge JS. Lumen formation during mammary epithelial morphogenesis: insights from in vitro and in vivo models. Cell Cycle. 2008;7(1):57–62.CrossRefPubMed
33.
Whelan KA, Caldwell SA, Shahriari KS, Jackson SR, Franchetti LD, Johannes GJ, Reginato MJ. Hypoxia suppression of Bim and Bmf blocks anoikis and luminal clearing during mammary morphogenesis. Mol Biol Cell. 2010;21(22):3829–37.CrossRefPubMedPubMedCentral
34.
Tancioni I, Miller NL, Uryu S, Lawson C, Jean C, Chen XL, Kleinschmidt EG, Schlaepfer DD. FAK activity protects nucleostemin in facilitating breast cancer spheroid and tumor growth. Breast Cancer Res. 2015;17:47.CrossRefPubMedPubMedCentral
35.
Bouchard V, Demers MJ, Thibodeau S, Laquerre V, Fujita N, Tsuruo T, Beaulieu JF, Gauthier R, Vezina A, Villeneuve L, et al. Fak/Src signaling in human intestinal epithelial cell survival and anoikis: differentiation state-specific uncoupling with the PI3-K/Akt-1 and MEK/Erk pathways. J Cell Physiol. 2007;212(3):717–28.CrossRefPubMed
36.
Zheng Y, Gierut J, Wang Z, Miao J, Asara JM, Tyner AL. Protein tyrosine kinase 6 protects cells from anoikis by directly phosphorylating focal adhesion kinase and activating AKT. Oncogene. 2013;32(36):4304–12.CrossRefPubMed
37.
Cowley GS, Weir BA, Vazquez F, Tamayo P, Scott JA, Rusin S, East-Seletsky A, Ali LD, Gerath WF, Pantel SE, et al. Parallel genome-scale loss of function screens in 216 cancer cell lines for the identification of context-specific genetic dependencies. Sci Data. 2014;1:140035.CrossRefPubMedPubMedCentral
Metadata
Title
SMARCE1 regulates metastatic potential of breast cancer cells through the HIF1A/PTK2 pathway
Authors
Aarti Sethuraman
Martin Brown
Tiffany N. Seagroves
Zhao-Hui Wu
Lawrence M. Pfeffer
Meiyun Fan
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2016
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-016-0738-9

Other articles of this Issue 1/2016

Breast Cancer Research 1/2016 Go to the issue

Research article

Naringenin prevents TGF-β1 secretion from breast cancer and suppresses pulmonary metastasis by inhibiting PKC activation

Editorial

Extending the Developmental Origins of Health and Disease theory: does paternal diet contribute to breast cancer risk in daughters?

Research article

Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus

Research article

Mcl-1 confers protection of Her2-positive breast cancer cells to hypoxia: therapeutic implications

Research article

Epigenetic silencing of CREB3L1 by DNA methylation is associated with high-grade metastatic breast cancers with poor prognosis and is prevalent in triple negative breast cancers

Meeting report

Complexity galore: 3D cultures, biomechanics and systems medicine at the eighth ENBDC workshop “Methods in Mammary Gland Development and Cancer”
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