nach oben

Breast Cancer Research and Treatment

Erschienen in:

28.05.2022 | Preclinical study

COL8A1 facilitates the growth of triple-negative breast cancer via FAK/Src activation

Erschienen in: Breast Cancer Research and Treatment | Ausgabe 2/2022

Einloggen, um Zugang zu erhalten

Abstract

Purpose

Triple-negative breast cancer (TNBC) is one of the most aggressive breast cancer subtypes, and treatment options are limited because of the lack of signature molecules and heterogeneous properties of cancer. COL8A1 expression is higher in breast cancer than in normal tissues and is strongly correlated with worse overall survival in patients with breast cancer. However, the biological function of COL8A1 on cancer progression is not fully understood. In this study, we investigated the biological function of COL8A1 on TNBC progression.

Methods

COL8A1-deficient cells were generated using the CRISPR-Cas9 system. The tumor growth and metastasis of TNBC cells were evaluated using three-dimensional culture (3D) methods and xenograft mouse models. The activation of focal adhesion kinase (FAK)/Src by COL8A1 in TNBC cells was evaluated by immunoblotting.

Results

COL8A1 expression was primarily distributed into TNBC cell lines. Further, relapse-free survival in TNBC patients with the MSL subtype was strongly associated with the COL8A1 expression. MDA-MB-231 and Hs578T cells, classified as the MSL subtype, strongly express COL8A1, and COL8A1 protein expression was induced by hypoxia in both cell lines. Loss of COL8A1 expression inhibited spheroid /tumor growth and metastasis in vitro and in vivo. Further, exogenous COL8A1 promoted TNBC growth via the FAK/Src activation. Finally, the spheroid growth of MDA-MB-231 and Hs578T cells was inhibited by defactinib, a FAK inhibitor, without cytotoxicity.

Conclusion

These results indicate that COL8A1-mediated FAK/Src activation produces a more aggressive phenotype in TNBC, and its target inhibition may be an efficacious treatment for TNBC.

Nur mit Berechtigung zugänglich

Rivenbark AG, O’Connor SM, Coleman WB (2013) Molecular and cellular heterogeneity in breast cancer: challenges for personalized medicine. Am J Pathol 183:1113–1124. https://doi.org/10.1016/j.ajpath.2013.08.002CrossRefPubMedPubMedCentral

Santonja A, Sánchez-Muñoz A, Lluch A et al (2018) Triple negative breast cancer subtypes and pathologic complete response rate to neoadjuvant chemotherapy. Oncotarget 9:26406–26416. https://doi.org/10.18632/oncotarget.25413

Lehmann BD, Bauer JA, Chen X et al (2011) Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 121:2750–2767. https://doi.org/10.1172/JCI45014CrossRefPubMedPubMedCentral

Charafe-Jauffret E, Ginestier C, Monville F et al (2006) Gene expression profiling of breast cell lines identifies potential new basal markers. Oncogene 25:2273–2284. https://doi.org/10.1038/sj.onc.1209254CrossRefPubMed

Bonnans C, Chou J, Werb Z (2014) Remodelling the extracellular matrix in development and disease. Nat Rev Mol Cell Biol 15:786–801CrossRef

Cox TR (2021) The matrix in cancer. Nat Rev Cancer 21:217–238. https://doi.org/10.1038/s41568-020-00329-7CrossRefPubMed

Kapoor R, Sakai LY, Funk S et al (1988) Type VIII collagen has a restricted distribution in specialized extracellular matrices. J Cell Biol 107:721–730. https://doi.org/10.1083/jcb.107.2.721CrossRefPubMed

Hopfer U, Fukai N, Hopfer H et al (2005) Targeted disruption of Col8a1 and Col8a2 genes in mice leads to anterior segment abnormalities in the eye. FASEB J 19:1232–1244. https://doi.org/10.1096/fj.04-3019comCrossRefPubMed

Shang J, Wang F, Chen P et al (2018) Co-expression network analysis identified COL8A1 is associated with the progression and prognosis in human colon adenocarcinoma. Dig Dis Sci 63:1219–1228. https://doi.org/10.1007/s10620-018-4996-5CrossRefPubMed

10.

Peng W, Di LJ, Zeng JJ et al (2020) Clinical value and potential mechanisms of COL8A1 upregulation in breast cancer: a comprehensive analysis. Cancer Cell Int 20:1–18. https://doi.org/10.1186/s12935-020-01465-8CrossRef

11.

Espinosa Fernandez JR, Eckhardt BL, Lee J et al (2020) Identification of triple-negative breast cancer cell lines classified under the same molecular subtype using different molecular characterization techniques: implications for translational research. PLoS ONE 15:1–8. https://doi.org/10.1371/journal.pone.0231953CrossRef

12.

Györffy B, Lanczky A, Eklund AC et al (2010) 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 123:725–731. https://doi.org/10.1007/s10549-009-0674-9CrossRefPubMed

13.

Tausendschön M, Rehli M, Dehne N et al (2015) Genome-wide identification of hypoxia-inducible factor-1 and -2 binding sites in hypoxic human macrophages alternatively activated by IL-10. Biochim Biophys Acta 1849:10–22. https://doi.org/10.1016/J.BBAGRM.2014.10.006CrossRefPubMed

14.

Adiguzel E, Hou G, Sabatini PJB, Bendeck MP (2013) Type VIII collagen signals via β1 integrin and RhoA to regulate MMP-2 expression and smooth muscle cell migration. Matrix Biol 32:332–341. https://doi.org/10.1016/j.matbio.2013.03.004CrossRefPubMed

15.

Hou G, Mulholland D, Gronska MA, Bendeck MP (2000) Type VIII collagen stimulates smooth muscle cell migration and matrix metalloproteinase synthesis after arterial injury. Am J Pathol 156:467–476. https://doi.org/10.1016/S0002-9440(10)64751-7CrossRefPubMedPubMedCentral

16.

Sulzmaier FJ, Jean C, Schlaepfer DD (2014) FAK in cancer: mechanistic findings and clinical applications. Nat Rev Cancer 14:598–610. https://doi.org/10.1038/nrc3792CrossRefPubMedPubMedCentral

17.

Gilkes DM, Semenza GL, Wirtz D (2014) Hypoxia and the extracellular matrix: drivers of tumour metastasis. Nat Rev Cancer 14:430–439. https://doi.org/10.1038/nrc3726CrossRefPubMedPubMedCentral

18.

Vaupel P, Mayer A (2007) Hypoxia in cancer: Significance and impact on clinical outcome. Cancer Metastasis Rev 26:225–239. https://doi.org/10.1007/s10555-007-9055-1CrossRefPubMed

19.

Vaupel P, Höckel M, Mayer A (2007) Detection and characterization of tumor hypoxia using pO₂ histography. Antioxidants Redox Signal 9:1221–1235. https://doi.org/10.1089/ars.2007.1628CrossRef

20.

Vaupel P, Mayer A, Höckel M (2004) Tumor hypoxia and malignant progression. Methods Enzymol 381:335–354. https://doi.org/10.1016/S0076-6879(04)81023-1CrossRefPubMed

21.

Boudreau NJ, Jones PL (1999) Extracellular matrix and integrin signalling: the shape of things to come. Biochem J 339:481–488CrossRef

22.

Mitra SK, Schlaepfer DD (2006) Integrin-regulated FAK-Src signaling in normal and cancer cells. Curr Opin Cell Biol 18:516–523. https://doi.org/10.1016/j.ceb.2006.08.011CrossRefPubMed

23.

López-Colomé AM, Lee-Rivera I, Benavides-Hidalgo R, López E (2017) Paxillin: a crossroad in pathological cell migration. J Hematol Oncol 10:1–15. https://doi.org/10.1186/s13045-017-0418-yCrossRef

24.

Nj T, Mo M, Cm K et al (2006) Alpha2(VIII) collagen substrata enhance endothelial cell retention under acute shear stress flow via an alpha2beta1 integrin-dependent mechanism: an in vitro and in vivo study. Circulation 114:820–829CrossRef

25.

Playford MP, Schaller MD (2004) The interplay between Src and integrins in normal and tumor biology. Oncogene 23:7928–7946. https://doi.org/10.1038/sj.onc.1208080CrossRefPubMed

26.

Santos ARCA, Corredor RG, Obeso BA et al (2012) β1 Integrin-focal adhesion kinase (FAK) signaling modulates retinal ganglion cell (RGC) survival. PLoS ONE 7:48332. https://doi.org/10.1371/journal.pone.0048332CrossRef

27.

Lee BY, Timpson P, Horvath LG, Daly RJ (2015) FAK signaling in human cancer as a target for therapeutics. Pharmacol Ther 146:132–149. https://doi.org/10.1016/j.pharmthera.2014.10.001CrossRefPubMed

28.

Curran CS, Carrillo ER, Ponik SM, Keely PJ (2015) Collagen density regulates xenobiotic and hypoxic response of mammary epithelial cells. Environ Toxicol Pharmacol 39:114–124. https://doi.org/10.1016/j.etap.2014.10.017CrossRefPubMed

29.

Earley S, Plopper GE (2006) Disruption of focal adhesion kinase slows transendothelial migration of AU-565 breast cancer cells. Biochem Biophys Res Commun 350:405–412. https://doi.org/10.1016/j.bbrc.2006.09.056CrossRefPubMed

30.

Golubovskaya VM, Virnig C, Cance WG (2008) TAE226-induced apoptosis in breast cancer cells with overexpressed Src or EGFR. Mol Carcinog 47:222–234. https://doi.org/10.1002/mc.20380CrossRefPubMed

Titel: COL8A1 facilitates the growth of triple-negative breast cancer via FAK/Src activation
Publikationsdatum: 28.05.2022
Erschienen in: Breast Cancer Research and Treatment / Ausgabe 2/2022
Print ISSN: 0167-6806
Elektronische ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-022-06635-y

Neu im Fachgebiet Onkologie

Umsetzung der POMGAT-Leitlinie läuft

03.05.2024 DCK 2024 Kongressbericht

Seit November 2023 gibt es evidenzbasierte Empfehlungen zum perioperativen Management bei gastrointestinalen Tumoren (POMGAT) auf S3-Niveau. Vieles wird schon entsprechend der Empfehlungen durchgeführt. Wo es im Alltag noch hapert, zeigt eine Umfrage in einem Klinikverbund.

Springer Medizin

COL8A1 facilitates the growth of triple-negative breast cancer via FAK/Src activation

Abstract

Purpose

Methods

Results

Conclusion

Neu im Fachgebiet Onkologie

Umsetzung der POMGAT-Leitlinie läuft

CUP-Syndrom: Künstliche Intelligenz kann Primärtumor finden

Sind Frauen die fähigeren Ärzte?

Adjuvante Immuntherapie verlängert Leben bei RCC

Update Onkologie

Springer Medizin

Abstract

Purpose

Methods

Results

Conclusion

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 2/2022

Breast cancer incidence and survival in Scotland by socio-economic deprivation and tumour subtype

Breast reconstruction and quality of life five years after cancer diagnosis: VICAN French National cohort

Stalled at the intersection: insurance status and disparities in post-mastectomy breast reconstruction

The risk of PD-L1 expression misclassification in triple-negative breast cancer

A comparative analysis of males and females with breast cancer undergoing mastectomy using the American College of Surgeon’s National Surgical Quality Improvement Project (NSQIP)

Accuracy of the Breast Cancer Surveillance Consortium Model Among Women with LCIS

Neu im Fachgebiet Onkologie

Umsetzung der POMGAT-Leitlinie läuft

CUP-Syndrom: Künstliche Intelligenz kann Primärtumor finden

Sind Frauen die fähigeren Ärzte?

Adjuvante Immuntherapie verlängert Leben bei RCC

Update Onkologie