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Molecular Diagnostics

Epigenetic activation of SOX11 is associated with recurrence and progression of ductal carcinoma in situ to invasive breast cancer

British Journal of Cancer (2024)Cite this article

Subjects

Abstract

Background

Risk of recurrence and progression of ductal carcinoma in situ (DCIS) to invasive cancer remains uncertain, emphasizing the need for developing predictive biomarkers of aggressive DCIS.

Methods

Human cell lines and mouse models of disease progression were analyzed for candidate risk predictive biomarkers identified and validated in two independent DCIS cohorts.

Results

RNA profiling of normal mammary and DCIS tissues (n = 48) revealed that elevated SOX11 expression correlates with MKI67, EZH2, and DCIS recurrence score. The 21T human cell line model of DCIS progression to invasive cancer and two mouse models developing mammary intraepithelial neoplasia confirmed the findings. AKT activation correlated with chromatin accessibility and EZH2 enrichment upregulating SOX11 expression. AKT and HER2 inhibitors decreased SOX11 expression along with diminished mammosphere formation. SOX11 was upregulated in HER2+ and basal-like subtypes (P < 0.001). Longitudinal DCIS cohort (n = 194) revealed shorter recurrence-free survival in SOX11+ than SOX11− patients (P = 0.0056 in all DCIS; P < 0.0001 in HER2+ subtype) associated with increased risk of ipsilateral breast event/IBE (HR = 1.9, 95%CI = 1.2–2.9; P = 0.003).

Discussion

Epigenetic activation of SOX11 drives recurrence of DCIS and progression to invasive cancer, suggesting SOX11 as a predictive biomarker of IBE.

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Fig. 1: Elevated SOX11 and EZH2 in DCIS with high DCIS recurrence score.
Fig. 2: Upregulation of SOX11 and EZH2 during progression of DCIS to invasive breast cancer in transgenic mouse models.
Fig. 3: Cell growth and mammosphere formation regulated by SOX11.
Fig. 4: Epigenetic mechanisms of SOX11 expression in DCIS-IDC cell line.
Fig. 5: Inhibitions of HER2 and AKT reduced cell growth and mammosphere formation with increased apoptosis.
Fig. 6: Elevated SOX11 expression in DCIS recurrence and progression to IDC.
Fig. 7: Proposed model of epigenetically elevated expression of SOX11 during recurrence of DCIS and progression to IDC.

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Data availability

NCBI GEO Super Series (GSE214094) are available with the accession numbers GSE214093 for Raw RCC files of nCounter expression and GSE213977 for ATAC-seq. Raw and normalized expression data will be available in GEO upon publication. Additional data that support the findings of this study is available in the SUPPLEMENTARY SECTION in the online supplement.

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Acknowledgements

We thank all the patients in the US and the UK who consented to share their tissue and clinical data for this study. We also acknowledge the collaborating institutions, and in particular the departments of pathology, personnel involved in banking, annotating tissues and processing data analysis. We also thank Dr. Akiko Sakai for her help in SOX11 promoter analysis.

Funding

This work was supported by grants to SS by MD Anderson Cancer Center, AMT by Cancer Research UK (C38317/A24043) and KWF Kankerbestrijding, EJS by Breast Cancer Now (TAP379) and Cancer Research UK (C38317/A24043), and MD Anderson core facility by NCI cancer center support grant (P30CA016672).

Author information

Authors and Affiliations

  1. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Warapen Treekitkarnmongkol, Kazuharu Kai, Hiroshi Katayama, Justin Wong, Farah A. Ladha, Tristian Nguyen, Wei Lu, Barbara Mino, Ximing Tang, Harsh Batra, Maria Gabriela Raso, Ignacio I. Wistuba & Subrata Sen

  2. School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, Guy’s Cancer Centre, King’s College London, London, UK

    Vandna Shah, Sarah E. Pinder & Elinor J. Sawyer

  3. Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA

    Brian Menegaz & Alastair M. Thompson

  4. Department of Anatomic Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Fei Yang & Savitri Krishnamurthy

  5. Department of Veterinary Medicine & Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Mihai Gagea

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  1. Warapen Treekitkarnmongkol
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Contributions

W. Treekitkarnmongkol: Conceptualization, formal analysis, supervision, investigation, methodology, writing–original draft, writing–review and editing. V. Shah: Data curation, formal analysis, validation, investigation, writing-review and editing. K. Kai: Conceptualization, formal analysis, investigation, writing–review and editing. H. Katayama: Conceptualization, formal analysis, validation, methodology, writing–review and editing. J. Wong: Software, formal analysis, investigation, methodology, writing–review and editing. F.A. Ladha: Data curation, validation, investigation. T. Nguyen: Data curation, validation, investigation. B. Menegaz: Resources, writing-review and editing. W. Lu: Investigation, methodology. F. Yang: Formal analysis, investigation, visualization. B. Mino: Investigation, methodology. X. Tang: Visualization, methodology. M. Gagea: Investigation, visualization. H. Batra: Data curation, visualization. M.G. Raso: Resources, data curation, visualization. I.I. Wistuba: Funding acquisition, writing–review and editing. S. Krishnamurthy: Formal analysis, investigation, visualization. S.E. Pinder: Conceptualization, resources, formal analysis, visualization, writing–review and editing. E.J. Sawyer: Conceptualization, resources, supervision, funding acquisition, writing–review and editing., A.M. Thompson: Conceptualization, resources, supervision, funding acquisition, project administration, writing–review and editing. S. Sen: Conceptualization, resources, supervision, funding acquisition, project administration, writing–review and editing.

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Correspondence to Alastair M. Thompson or Subrata Sen.

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Treekitkarnmongkol, W., Shah, V., Kai, K. et al. Epigenetic activation of SOX11 is associated with recurrence and progression of ductal carcinoma in situ to invasive breast cancer. Br J Cancer (2024). https://doi.org/10.1038/s41416-024-02697-5

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