RBCK1 drives breast cancer cell proliferation by promoting transcription of estrogen receptor alpha and cyclin B1.
Cell cycle regulatory pathways in breast cancer are incompletely described. Here, we report an important role in estrogen receptor alpha (ERalpha)-positive breast cancer cells for the protein kinase C1 (PKC1)-interacting protein RBCK1 in supporting cell cycle progression by driving transcription of ERalpha and cyclin B1. RBCK1-depleted cells exhibited increased accumulation in G(2)-M phase of the cell cycle, decreased proliferation, and reduced mRNA levels for ERalpha and its target genes cyclin D1 and c-myc. Chromatin immunoprecipitation revealed that ERalpha transcription is associated with RBCK1 recruitment to the ERalpha promoter, suggesting that transcriptional regulation is one mechanism by which RBCK1 affects ERalpha mRNA levels. G(2)-M phase arrest was mediated independently from reduced ERalpha levels, instead associated with transcriptional inhibition of the key G(2)-M regulator cyclin B1. In breast tumor samples, there was a positive correlation between levels of RBCK1, ERalpha, and cyclin B1 mRNA levels. Our findings suggest that RBCK1 regulates cell cycle progression and proliferation of ERalpha-positive breast cancer cells by supporting transcription of ERalpha and cyclin B1.
Gustafsson
Nina
N
Department of Biosciences and Nutrition, Karolinska Institute, Novum, S-141 57 Huddinge, Sweden. nina.gustafsson@ki.se
Zhao
Chunyan
C
Gustafsson
Jan-Ake
JA
Dahlman-Wright
Karin
K
D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle; D002455:Cell Division; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D056744:Cyclin B1 / Q000235:genetics* / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D005260:Female; D016193:G1 Phase; D016195:G2 Phase; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008954:Models, Biological; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D034622:RNA Interference; D016192:Resting Phase, Cell Cycle; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D044767:Ubiquitin-Protein Ligases
D056744:Cyclin B1; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D014157:Transcription Factors; C504507:RBCK1 protein, human; D044767:Ubiquitin-Protein Ligases