Gossypol Inhibits GLI3-dependent SHH Signaling to Selectively Target SPOP-deficient Breast Cancer Cells

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Breast cancer is a leading cause of cancer mortality in women.
• Molecular heterogeneity in breast cancer impacts treatment efficacy.
• Speckle-type POZ protein (SPOP) is frequently downregulated in breast cancer, but its role in oncogenesis is unclear.

Purpose of the Study:

• To investigate the role of SPOP deficiency in breast cancer progression.
• To identify therapeutic vulnerabilities in SPOP-deficient breast cancers.
• To explore the link between SPOP loss and Sonic Hedgehog (SHH) signaling.

Main Methods:

• SPOP knockdown was performed in MCF-7 breast cancer cells.
• Effects on cell proliferation and SHH signaling were assessed.
• A natural compound library was screened for agents targeting SPOP-deficient cells, with efficacy evaluated by cell viability, gene expression, and clonogenic growth assays.

Main Results:

• SPOP knockdown increased cell proliferation and hyperactivated GLI3-dependent SHH signaling.
• Gossypol was identified as a selective inhibitor of SPOP-deficient cells.
• Gossypol reduced viability, suppressed GLI3 target gene expression, and impaired clonogenic growth in SPOP-deficient cells.

Conclusions:

• SPOP loss promotes breast cancer progression through GLI3-dependent SHH signaling.
• Gossypol demonstrates potential as a targeted therapy for SPOP-deficient breast cancers.