Epigenetic Activation of SOX11 Is Associated With Recurrence and Progression of Ductal Carcinoma In Situ to Invasive Breast Cancer

Authors

Warapen Treekitkarnmongkol
Vandna Shah
Kazuharu Kai
Hiroshi Katayama
Justin Wong
Farah A Ladha
Tristian Nguyen
Brian Menegaz
Wei Lu
Fei Yang
Barbara Mino
Ximing Tang
Mihai Gagea
Harsh Batra
Maria Gabriela Raso
Ignacio I Wistuba
Savitri Krishnamurthy
Sarah E Pinder
Elinor J Sawyer
Alastair M Thompson
Subrata Sen

Publication Date

7-1-2024

Journal

British Journal of Cancer

DOI

10.1038/s41416-024-02697-5

PMID

38760444

PMCID

PMC11231151

PubMedCentral® Posted Date

5-17-2024

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Humans, Female, Breast Neoplasms, Animals, Carcinoma, Intraductal, Noninfiltrating, SOXC Transcription Factors, Mice, Disease Progression, Neoplasm Recurrence, Local, Epigenesis, Genetic, Cell Line, Tumor, Neoplasm Invasiveness, Biomarkers, Tumor, Gene Expression Regulation, Neoplastic, Receptor, ErbB-2, Enhancer of Zeste Homolog 2 Protein

Published Open-Access

yes

Recommended Citation

Treekitkarnmongkol, Warapen; Shah, Vandna; Kai, Kazuharu; et al., "Epigenetic Activation of SOX11 Is Associated With Recurrence and Progression of Ductal Carcinoma In Situ to Invasive Breast Cancer" (2024). Faculty, Staff and Student Publications. 1987.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/1987