Differential gene expression analysis of palbociclib-resistant TNBC via RNA-seq

Abstract

Purpose The management of triple-negative breast cancer (TNBC) remains a significant clinical challenge due to the lack of effective targeted therapies. Inhibitors of the cyclin-dependent kinases 4 and 6 (CDK4/6) are emerging as promising therapeutic agents against TNBC; however, cells can rapidly acquire resistance through multiple mechanisms that are yet to be identified. Therefore, determining the mechanisms underlying resistance to CDK4/6 inhibition is crucial to develop combination therapies that can extend the efficacy of the CDK4/6 inhibitors or delay resistance. This study aims to identify differentially expressed genes (DEG) associated with acquired resistance to palbociclib in ER− breast cancer cells. Methods We performed next-generation transcriptomic sequencing (RNA-seq) and pathway analysis in ER− MDA-MB-231 palbociclib-sensitive (231/pS) and palbociclib-resistant (231/pR) cells. Results We identified 2247 up-regulated and 1427 down-regulated transcripts in 231/pR compared to 231/pS cells. DEGs were subjected to functional analysis using Gene Ontology (GO) and the KEGG database which identified many transduction pathways associated with breast cancer, including the PI3K/AKT, PTEN and mTOR pathways. Additionally, Ingenuity Pathway Analysis (IPA) revealed that resistance to palbociclib is closely associated with altered cholesterol and fatty acid biosynthesis suggesting that resistance to palbociclib may be dependent on lipid metabolic reprograming. Conclusion This study provides evidence that lipid metabolism is altered in TNBC with acquired resistance to palbociclib. Further studies are needed to determine if the observed lipid metabolic rewiring can be exploited to overcome therapy resistance in TNBC.

The PRC2.1 Subcomplex Opposes G1 Progression through Regulation of CCND1 and CCND2

“…PCA analysis of our RNA-Seq experiment revealed substantial shifts in variance between palbociclib-treated and Mock-treated samples for each genotype (Fig. S3A, bottom), suggesting that exposure to palbociclib resulted in changes in gene expression, consistent with previous reports 86,87 . However, the PCA of our CUT&RUN experiment did not reveal large differences in H3K27me3 distribution between palbociclib-treated and untreated samples (Fig.…”

“…While D-type cyclins are necessary to activate the kinase activity of CDK4/6, they have also been shown to play roles outside of the RB1-E2F pathway [87][88][89] . We sought to test if CDK4/6 activity was increased in MTF2∆.…”

Editorial: Reviews and advances in the molecular mechanisms of breast cancer

“…ERβ1 reversed this effect, with a consequent increase in oxidative phosphorylation and downregulation of cholesterol biosynthesis. Further, we note that upregulation of cholesterol biosynthesis is a key pathway in CDK4/6i resistance ( Lanceta et al, 2021 ) and can also influence the immune microenvironment ( Bai et al, 2024 ). Finally, invasion and metastasis , including the related process of EMT, frequently recurs.…”

Silibinin, Synergistically Enhances Vinblastine-Mediated Apoptosis in Triple Negative Breast Cancer Cell Line: Involvement of Bcl2/Bax and Caspase-3 Pathway

“…Lack of progesterone receptor (PR), estrogen receptor (ER), and human epidermal growth factor receptor 2 (HER2) characterize a heterogeneous subtype of breast cancer known as Triple-negative breast cancer (TNBC). Although TNBC comprises only 15-20% of all diagnosed breast cancer patients, it is associated with a poor prognosis, metastasis, and a high recurrence rate 1 , 2 . Due to lack of receptors expression, TNBC is unresponsive to targeted therapies, and management of this type has been mainly limited to chemotherapy and surgery 3 .…”