TGFB2-AS1 Inhibits Triple-negative Breast Cancer Progression Via Interaction with SMARCA4 and Regulating Its Targets and

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2022 Sep 20

PMID 36126099

Authors

Cixiang Zhou

Difei Wang

Jingchi Li

Qiuyu Wang

Lulu Wo

Xin Zhang

Zhexuan Hu

Zheng Wang

Mengna Zhan

Ming He

Guohong Hu

Xiaosong Chen

Kunwei Shen

Guo-Qiang Chen

Qian Zhao

Affiliations

Soon will be listed here.

Abstract

Triple-negative breast cancer (TNBC) is the most challenging breast cancer subtype for its high rates of relapse, great metastatic potential, and short overall survival. How cancer cells acquire metastatic potency through the conversion of noncancer stem-like cells into cancer cells with stem-cell properties is poorly understood. Here, we identified the long noncoding RNA (lncRNA) TGFB2-AS1 as an important regulator of the reversibility and plasticity of noncancer stem cell populations in TNBC. We revealed that TGFB2-AS1 impairs the breast cancer stem-like cell (BCSC) traits of TNBC cells in vitro and dramatically decreases tumorigenic frequency and lung metastasis in vivo. Mechanistically, TGFB2-AS1 interacts with SMARCA4, a core subunit of the SWI/SNF chromatin remodeling complex, and results in transcriptional repression of its target genes including and in an or way, leading to inhibition of transforming growth factor β (TGFβ) signaling and BCSC characteristics. In line with this, TGFB2-AS1 overexpression in an orthotopic TNBC mouse model remarkably abrogates the enhancement of tumor growth and lung metastasis endowed by TGFβ2. Furthermore, combined prognosis analysis of TGFB2-AS1 and TGFβ2 in TNBC patients shows that high TGFB2-AS1 and low TGFβ2 levels are correlated with better outcome. These findings demonstrate a key role of TGFB2-AS1 in inhibiting disease progression of TNBC based on switching the cancer cell fate of TNBC and also shed light on the treatment of TNBC patients.

Citing Articles

LINC00899 suppresses the progression of triple-negative breast cancer via the miRNA-425/PTEN axis and is a biomarker for neoadjuvant chemotherapy efficacy.

Niu L, Bai Y, Yu M, Sun X J Cancer. 2025; 16(5):1647-1655.

PMID: 39991583 PMC: 11843232. DOI: 10.7150/jca.100619.

FBF1 maintains stem cell-like properties in breast cancer via PI3K/AKT/SOX2 axis.

Guo C, Li S, Liu J, Ma Y, Liang A, Lou Y Stem Cell Res Ther. 2025; 16(1):83.

PMID: 39988656 PMC: 11849350. DOI: 10.1186/s13287-025-04194-9.

Long Non-Coding RNAs: Key Regulators of Tumor Epithelial/Mesenchymal Plasticity and Cancer Stemness.

Yuan Y, Tang Y, Fang Z, Wen J, Wicha M, Luo M Cells. 2025; 14(3).

PMID: 39937018 PMC: 11817775. DOI: 10.3390/cells14030227.

Glycosylation profiling of triple-negative breast cancer: clinical and immune correlations and identification of LMAN1L as a biomarker and therapeutic target.

Yu Q, Zhong H, Zhu X, Liu C, Zhang X, Wang J Front Immunol. 2025; 15:1521930.

PMID: 39867909 PMC: 11759290. DOI: 10.3389/fimmu.2024.1521930.

Discovery of novel serum peptide biomarkers for cholangiocarcinoma recurrence through MALDI-TOF MS and LC-MS/MS peptidome analysis.

Thanasukarn V, Prajumwongs P, Muangritdech N, Loilome W, Namwat N, Klanrit P Sci Rep. 2025; 15(1):2582.

PMID: 39833435 PMC: 11746940. DOI: 10.1038/s41598-025-87124-2.

References

Oskarsson T, Batlle E, Massague J . Metastatic stem cells: sources, niches, and vital pathways. Cell Stem Cell. 2014; 14(3):306-21. PMC: 3998185. DOI: 10.1016/j.stem.2014.02.002. View

Chabanon R, Morel D, Postel-Vinay S . Exploiting epigenetic vulnerabilities in solid tumors: Novel therapeutic opportunities in the treatment of SWI/SNF-defective cancers. Semin Cancer Biol. 2019; 61:180-198. DOI: 10.1016/j.semcancer.2019.09.018. View

Tay Y, Rinn J, Pandolfi P . The multilayered complexity of ceRNA crosstalk and competition. Nature. 2014; 505(7483):344-52. PMC: 4113481. DOI: 10.1038/nature12986. View

Liu R, Liu H, Chen X, Kirby M, Brown P, Zhao K . Regulation of CSF1 promoter by the SWI/SNF-like BAF complex. Cell. 2001; 106(3):309-18. DOI: 10.1016/s0092-8674(01)00446-9. View

Gupta R, Shah N, Wang K, Kim J, Horlings H, Wong D . Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 2010; 464(7291):1071-6. PMC: 3049919. DOI: 10.1038/nature08975. View

Shain A, Pollack J . The spectrum of SWI/SNF mutations, ubiquitous in human cancers. PLoS One. 2013; 8(1):e55119. PMC: 3552954. DOI: 10.1371/journal.pone.0055119. View

Massague J . TGFbeta in Cancer. Cell. 2008; 134(2):215-30. PMC: 3512574. DOI: 10.1016/j.cell.2008.07.001. View

Padmanaban V, Krol I, Suhail Y, Szczerba B, Aceto N, Bader J . E-cadherin is required for metastasis in multiple models of breast cancer. Nature. 2019; 573(7774):439-444. PMC: 7365572. DOI: 10.1038/s41586-019-1526-3. View

Derynck R, Turley S, Akhurst R . TGFβ biology in cancer progression and immunotherapy. Nat Rev Clin Oncol. 2020; 18(1):9-34. PMC: 9721352. DOI: 10.1038/s41571-020-0403-1. View

10.

Garrido-Castro A, Lin N, Polyak K . Insights into Molecular Classifications of Triple-Negative Breast Cancer: Improving Patient Selection for Treatment. Cancer Discov. 2019; 9(2):176-198. PMC: 6387871. DOI: 10.1158/2159-8290.CD-18-1177. View

11.

Wu Q, Lian J, Stein J, Stein G, Nickerson J, Imbalzano A . The BRG1 ATPase of human SWI/SNF chromatin remodeling enzymes as a driver of cancer. Epigenomics. 2017; 9(6):919-931. PMC: 5705788. DOI: 10.2217/epi-2017-0034. View

12.

Minn A, Gupta G, Siegel P, Bos P, Shu W, Giri D . Genes that mediate breast cancer metastasis to lung. Nature. 2005; 436(7050):518-24. PMC: 1283098. DOI: 10.1038/nature03799. View

13.

Shaw F, Harrison H, Spence K, Ablett M, Simoes B, Farnie G . A detailed mammosphere assay protocol for the quantification of breast stem cell activity. J Mammary Gland Biol Neoplasia. 2012; 17(2):111-7. DOI: 10.1007/s10911-012-9255-3. View

14.

Mittal P, Roberts C . The SWI/SNF complex in cancer - biology, biomarkers and therapy. Nat Rev Clin Oncol. 2020; 17(7):435-448. PMC: 8723792. DOI: 10.1038/s41571-020-0357-3. View

15.

J van t Veer L, Dai H, van de Vijver M, He Y, Hart A, Mao M . Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002; 415(6871):530-6. DOI: 10.1038/415530a. View

16.

Quinn J, Jones M, Okimoto R, Nanjo S, Chan M, Yosef N . Single-cell lineages reveal the rates, routes, and drivers of metastasis in cancer xenografts. Science. 2021; 371(6532). PMC: 7983364. DOI: 10.1126/science.abc1944. View

17.

Stankic M, Pavlovic S, Chin Y, Brogi E, Padua D, Norton L . TGF-β-Id1 signaling opposes Twist1 and promotes metastatic colonization via a mesenchymal-to-epithelial transition. Cell Rep. 2013; 5(5):1228-42. PMC: 3891470. DOI: 10.1016/j.celrep.2013.11.014. View

18.

Leppek K, Stoecklin G . An optimized streptavidin-binding RNA aptamer for purification of ribonucleoprotein complexes identifies novel ARE-binding proteins. Nucleic Acids Res. 2013; 42(2):e13. PMC: 3902943. DOI: 10.1093/nar/gkt956. View

19.

Apostolou E, Hochedlinger K . Chromatin dynamics during cellular reprogramming. Nature. 2013; 502(7472):462-71. PMC: 4216318. DOI: 10.1038/nature12749. View

20.

Afgan E, Baker D, van den Beek M, Blankenberg D, Bouvier D, cech M . The Galaxy platform for accessible, reproducible and collaborative biomedical analyses: 2016 update. Nucleic Acids Res. 2016; 44(W1):W3-W10. PMC: 4987906. DOI: 10.1093/nar/gkw343. View