ABSTRACT
Triple-negative breast cancer (TNBC), the most aggressive subtype of breast cancer, has a poor prognosis and lacks effective treatment strategies. Here, the study discovered that TNBC shows a decreased expression of epithelial transcription factor ovo-like 2 (OVOL2). The loss of OVOL2 promotes fatty acid oxidation (FAO), providing additional energy and NADPH to sustain stemness characteristics, including sphere-forming capacity and tumor initiation. Mechanistically, OVOL2 not only suppressed STAT3 phosphorylation by directly inhibiting JAK transcription but also recruited histone deacetylase 1 (HDAC1) to STAT3, thereby reducing the transcriptional activation of downstream genes carnitine palmitoyltransferase1 (CPT1A and CPT1B). PyVT-Ovol2 knockout mice develop a higher number of primary breast tumors with accelerated growth and increased lung-metastases. Furthermore, treatment with FAO inhibitors effectively reduces stemness characteristics of tumor cells, breast tumor initiation, and metastasis, especially in OVOL2-deficient breast tumors. The findings suggest that targeting JAK/STAT3 pathway and FAO is a promising therapeutic strategy for OVOL2-deficient TNBC.
Subject(s)
Fatty Acids , Oxidation-Reduction , STAT3 Transcription Factor , Triple Negative Breast Neoplasms , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/metabolism , Triple Negative Breast Neoplasms/pathology , Animals , Mice , Female , Fatty Acids/metabolism , Humans , STAT3 Transcription Factor/metabolism , STAT3 Transcription Factor/genetics , Mice, Knockout , Carnitine O-Palmitoyltransferase/genetics , Carnitine O-Palmitoyltransferase/metabolism , Cell Line, Tumor , Disease Models, Animal , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathologyABSTRACT
An intramolecular ring expansion of in situ formed 3-silaazetidine with internal alkynes has been developed via Pd-catalyzed Si-C bond activation. The reaction gives rise to 6,5- and 6,6-fused bicyclic 1,3-azasilines, in which the silicon atom locates at the ring junction position.
ABSTRACT
A nonracemic 3-silyl-3-borylhex-4-enoate reagent has been developed. Its asymmetric crotylboration of aldehydes provides Z-anti-homoallylic alcohols possessing a trisubstituted vinylsilane in high yields with excellent stereo- and enantioselectivity. Diverse decoration of vinylsilane and ester groups, as well as formation of functionalized THF rings, showcase the potential of the approach in the synthesis of polyketide natural products.