Abstract: Background: Breast cancer (BRCA) is characterized by high heterogeneity, with aggressive subtypes frequently showing poor prognosis and resistance to conventional therapies, making the discovery of new therapeutic targets and strategies imperative. While elevated expression of Discs Large Homolog 3 (DLG3) has been reported in BRCA, its functional role in disease progression remains unclear.
Methods: We performed bioinformatic analyses of clinical datasets to evaluate the prognostic significance of DLG3 expression in BRCA patients. In vitro gain and loss-of-function experiments were conducted to assess the impact of DLG3 on BRCA cell proliferation, migration, and colony formation. Transcriptomic profiling, coupled with pharmacological inhibition, was employed to identify and validate downstream signaling pathways. Additionally, we extended our validation to an in vivo model to assess the role of DLG3 in tumor progression.
Results: DLG3 overexpression significantly promoted cell proliferation and migration in ER-positive MCF7 and triple-negative MDA-MB-231 breast cancer cells, whereas its knockdown suppressed these effects. Transcriptomic analyses revealed that DLG3 activates STAT3 signaling, a finding further corroborated by Western blot. Critically, treatment with the STAT3 inhibitor Stattic attenuated DLG3-driven proliferation and migration, supporting a DLG3–STAT3 oncogenic axis. Furthermore, in vivo studies validated the role of DLG3 in promoting tumor growth and its correlation with elevated STAT3 signaling, consistent with our in vitro findings.
Conclusion: Our findings establish DLG3 as a novel driver of breast cancer progression that directly activates STAT3 signaling. DLG3 thus represents both a potential prognostic biomarker and a promising therapeutic target for aggressive breast cancer subtypes, including triple-negative breast cancer.