diptoindonesin-g and Breast-Neoplasms

HSP90 inhibitors can target many oncoproteins simultaneously, but none have made it through clinical trials due to dose-limiting toxicity and induction of heat shock response, leading to clinical resistance. We identified diptoindonesin G (dip G) as an HSP90 modulator that can promote degradation of HSP90 clients by binding to the middle domain of HSP90 (K

Topics: Antineoplastic Agents; Benzofurans; Breast Neoplasms; Cell Proliferation; Female; HSP90 Heat-Shock Proteins; Humans; Mutation

Breast cancer is a heterogeneous disease that includes different molecular subtypes. The basal-like subtype has a poor prognosis and a high recurrence rate, whereas the luminal-like subtype confers a more favorable patient prognosis partially due to anti-hormone therapy responsiveness. Here, we demonstrate that diptoindonesin G (Dip G), a natural product, exhibits robust differentiation-inducing activity in basal-like breast cancer cell lines and animal models. Specifically, Dip G treatment caused a partial transcriptome shift from basal to luminal gene expression signatures and prompted sensitization of basal-like breast tumors to tamoxifen therapy. Dip G upregulated the expression of both GABARAPL1 (GABA

Topics: Adaptor Proteins, Signal Transducing; Animals; Benzofurans; Breast Neoplasms; Cell Differentiation; Cell Line, Tumor; China; Estrogen Receptor beta; Female; Gene Expression; Gene Expression Regulation, Neoplastic; Humans; Mice; Mice, Inbred BALB C; Microtubule-Associated Proteins; Neoplasm Recurrence, Local; Neoplasms, Basal Cell; Prognosis; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Tamoxifen

ERβ is regarded as a "tumor suppressor" in breast cancer due to its anti-proliferative effects. However, unlike ERα, ERβ has not been developed as a therapeutic target in breast cancer due to loss of ERβ in aggressive cancers. In a small-molecule library screen for ERβ stabilizers, we identified Diptoindonesin G (Dip G), which significantly increases ERβ protein stability while decreasing ERα protein levels. Dip G enhances the transcription and anti-proliferative activities of ERβ, while attenuating the transcription and proliferative effects of ERα. Further investigation revealed that instead of targeting ER, Dip G targets the CHIP E3 ubiquitin ligase shared by ERα and ERβ. Thus, Dip G is a dual-functional moiety that reciprocally controls ERα and ERβ protein stability and activities via an indirect mechanism. The ERβ stabilization effects of Dip G may enable the development of ERβ-targeted therapies for human breast cancers.

Topics: Benzofurans; Blotting, Western; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Gene Expression Regulation, Neoplastic; Humans; Molecular Docking Simulation; Protein Stability; Small Molecule Libraries; Structure-Activity Relationship