Cancer-associated adipocytes confer CDK4/6 inhibitor resistance in ER+ breast cancer through an IL-6/STAT3/SREBF2 axis coupled with cholesterol metabolism and cell cycle reprogramming
Huang R., Tong Y., Sun X., Wang H., Wang Z., Tang Y.
Animal Study, published in Int J Biol Sci (2026) — summary generated from the PubMed abstract.
Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.
- Level A · Stronger Clinical Evidence
- Level B · Emerging clinical evidence with positive signals
- Level C · Early human research exploring benefits
- Level D · Scientific groundwork from lab and animal studies
- Emerging · Emerging topic under active research
This page is generated from the PubMed record. The Thai description is an automated summary of bibliographic fields and the abstract, not a full translation, and is not medical advice.
- Study type
- Animal Study
- Journal
- Int J Biol Sci (2026)
- Reported sample size
- —
- Source database
- Europe PMC
- PMID
- 42328452
- PMCID
- PMC13282890
- DOI
- 10.7150/ijbs.130653
Abstract (original English)
Cancer-associated adipocytes (CAAs) within the tumor microenvironment (TME) critically regulate oncogenic progression. However, the mechanistic basis underlying CAAs-mediated CDK4/6 inhibitor (CDK4/6i) resistance in estrogen receptor-positive (ER+) breast cancer remains elusive. In this study, we revealed that CAAs supernatant demonstrated enhanced capacity to induce CDK4/6i resistance in ER+ breast cancer cells compared to NAs-derived conditioned medium. Through integrated RNA sequencing and cytokine microarray screening, we identified marked upregulation of IL-6 in both CAAs and their conditioned media. Mechanistically, CAAs-derived IL-6 activates the JAK-STAT3 axis, leading to transcriptional upregulation of SREBF2, which directly drives CDK4/6i resistance through HMGCR-mediated lipid metabolism and CDKN2C-mediated cell cycle progression (IL-6 - STAT3 - SREBF2-HMGCR/CDKN2C axis). Reciprocally, breast cancer cell-secreted exosomal miR-1246 promotes the transformation of normal adipocytes (NAs) to CAAs via PAX5-dependent regulation, and CAAs highly express UCHL1, which stabilizes KLF5 through K48-linked deubiquitination to activate NF-κB signaling, thereby augmenting IL-6 production (exosomal miR-1246-PAX5 and UCHL1-KLF5-NF-κB loop). Pharmacologic inhibition of HMGCR with simvastatin, alone or combined with IL-6 blockade, restored CDK4/6i sensitivity in vitro and in vivo, high
What this study does not prove
- • This study does not prove SVF is an approved treatment or a replacement for standard care.
- • This is preclinical work; animal or laboratory results cannot be applied to humans.
Evidence level
Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.
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