Abstract
<title>Abstract</title> <p>Background Breast cancer poses a severe global public health burden, where tumor progression, metastasis and chemoresistance substantially compromise therapeutic outcomes. Metabolic reprogramming, particularly aberrant fatty acid metabolism, facilitates malignant transformation and drug resistance. Nevertheless, the key molecular mediators linking lipid remodeling to breast cancer advancement and paclitaxel resistance remain largely uncharacterized. Methods We analyzed FAM155B expression and clinical significance via public transcriptomic data and clinical specimens. Gain/loss-of-function assays assessed its roles in tumor growth, metastasis and paclitaxel sensitivity. RNA-seq, qPCR, immunoblotting and BODIPY staining detected lipid metabolic changes, while rescue experiments validated SREBP1 and fatty acid synthesis downstream of FAM155B. Bioinformatics, luciferase and ChIP-qPCR assays confirmed BPTF-mediated transcriptional activation of FAM155B. Results The expression level of FAM155B was significantly upregulated in breast cancer tissues and cell lines, and elevated FAM155B expression was closely correlated with advanced clinical stages and unfavorable patient prognosis. Functional validation experiments demonstrated that FAM155B exerts oncogenic effects by facilitating the proliferation, migration, and invasion of breast cancer cells, as well as promoting xenograft tumor growth in vivo. Mechanistically, FAM155B activates the fatty acid biosynthesis program, leading to increased free fatty acids and lipid droplet accumulation. Further mechanistic investigations identified SREBP1 as a critical downstream mediator responsible for FAM155B-regulated lipid metabolic reprogramming. In addition, the chromatin remodeler BPTF was verified to directly bind to the promoter region of FAM155B, thereby transcriptionally activating FAM155B expression and driving lipid remodeling and malignant progression of breast cancer. Moreover, genetic depletion of FAM155B markedly enhanced the chemosensitivity of breast cancer cells to paclitaxel treatment both in vitro and in vivo. Conclusions Collectively, FAM155B drives breast cancer progression and paclitaxel resistance. The BPTF/FAM155B/SREBP1 axis facilitates tumor progression and paclitaxel resistance via fatty acid metabolic reprogramming, and targeting this cascade holds therapeutic potential to enhance taxane chemotherapy efficacy.</p>