Palbociclib enhances activin‐SMAD‐induced cytostasis in estrogen receptor‐positive breast cancer

Abstract

Cyclin‐dependent kinase (CDK) 4 and CDK6 inhibitors are effective therapeutic options for hormone receptor (HR)‐positive, human epidermal growth factor receptor 2 (HER2)‐negative advanced breast cancer. Although CDK4/6 inhibitors mainly target the cyclin D‐CDK4/6‐retinoblastoma tumor suppressor protein (RB) axis, little is known about the clinical impact of inhibiting phosphorylation of other CDK4/6 target proteins. Here, we focused on other CDK4/6 targets, SMAD proteins. We showed that a CDK4/6 inhibitor palbociclib and activin‐SMAD2 signaling cooperatively inhibited cell cycle progression of a luminal‐type breast cancer cell line T47D. Palbociclib enhanced SMAD2 binding to the genome by inhibiting CDK4/6‐mediated linker phosphorylation of the SMAD2 protein. We also showed that cyclin G2 plays essential roles in SMAD2‐dependent cytostatic response. Moreover, comparison of the SMAD2 ChIP‐seq data of T47D cells with those of Hs578T (triple‐negative breast cancer cells) indicated that palbociclib augmented different SMAD2‐mediated functions based on cell type, and enhanced SMAD2 binding to the target regions on the genome without affecting its binding pattern. In summary, palbociclib enhances the cytostatic effects of the activin‐SMAD2 signaling pathway, whereas it possibly strengthens the tumor‐promoting aspect in aggressive breast cancer.

A new glioma grading model based on histopathology and Bone Morphogenetic Protein 2 mRNA expression

“…When BMPs bind to the complex, the type II receptor phosphorylates the glycine-serine (GS) region of the type I receptor, causing a conformational change and thus activation of the type I receptor, which in-turn activates the Receptor-associated SMAD (R-SMAD) protein. Following activation, the R-SMAD protein can form heterologous complexes with Smad4 in the cytoplasm and enter the nucleolus through the MH2 domain to regulate the transcription of target genes 22 – 25 . During development, the expression of BMPR transited from fetal type (BMPR1A) which induced the proliferation of neuroepithelial cells to adult type receptor type (BMPR1B) which mediated the differentiation of astrocytes and neurons.…”

Anti‐pyroptotic function of TGF‐β is suppressed by a synthetic dsRNA analogue in triple negative breast cancer cells

“…Anti-Smad2 ChIP sequence data from Hs578T cells stimulated with activin A were obtained in our previous study (GEO, accession number GSM3301952) [28]. Smad2 binding at the target gene locus was shown using the UCSC Genome Browser on Human Dec. 2013 (GRCh38/hg38) Assembly.…”

“…The gRNA sequences for each gene or control gRNA [29] are described in Table S2. caSmad3 cDNA and CSII-CAG-MCS-IRES-puro lentiviral vector were described previously [28]. Briefly, caSmad3 or HA control tag was subcloned into the multiple cloning site (MCS) of CSII-CAG-MCS-IRES-puro lentiviral vector, which is originated from CSII-EF-RfA to express the inserted cDNA driven by CAG promoter.…”

“…S5I). To investigate the possibility of transcriptional repression by the Smad pathway downstream of TGF-b, we reanalyzed the Smad2 ChIP sequence data in Hs578T cells stimulated with the TGF-b family ligand activin A [28]. We identified a Smad2 binding site in the promoter region of the PMAIP1 gene encoding Noxa in Hs578T cells (Fig.…”

Tyrosine kinase Eph receptor A6 sensitizes glioma‐initiating cells towards bone morphogenetic protein‐induced apoptosis

“…Patients were divided into tertiles based on their mRNA expression levels. Differences between groups were evaluated by the log‐rank test using the R package cmprsk as described previously …”