RB1 loss induces quiescent state through downregulation of RAS signaling in mammary epithelial cells

• Published in: Cancer science Vol. 115; no. 5; pp. 1576 - 1586
• Main Authors: Gong, Linxiang, Voon, Dominic Chih-Cheng, Nakayama, Joji, Takahashi, Chiaki, Kohno, Susumu
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.05.2024; John Wiley and Sons Inc
• Subjects: Antibodies; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Cell cycle; Cell Line, Tumor; Cyclin-dependent kinase inhibitor p27; Cyclin-Dependent Kinase Inhibitor p27 - genetics; Cyclin-Dependent Kinase Inhibitor p27 - metabolism; Cyclin-dependent kinases; Cyclins; DNA damage; Down-Regulation; Epithelial cells; Epithelial Cells - metabolism; Epithelial-Mesenchymal Transition - genetics; Farnesyltransferase; Female; Humans; Infections; Kinases; Mammary gland; Mammary Glands, Human - cytology; Mammary Glands, Human - metabolism; Mammary Glands, Human - pathology; MAP kinase; Myc protein; Original; ORIGINAL ARTICLES; Ovaries; Proteins; ras Proteins - genetics; ras Proteins - metabolism; Retinoblastoma; Retinoblastoma Binding Proteins - genetics; Retinoblastoma Binding Proteins - metabolism; Retinoblastoma Protein - genetics; Retinoblastoma Protein - metabolism; Senescence; Signal Transduction; Small cell lung carcinoma; Transcription factors; Tumor suppressor genes; Tumors; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; RB1; RBL2/p130; quiescence; RAS; MYC
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.16122

While loss of function (LOF) of retinoblastoma 1 (RB1) tumor suppressor is known to drive initiation of small-cell lung cancer and retinoblastoma, RB1 mutation is rarely observed in breast cancers at their initiation. In this study, we investigated the impact on untransformed mammary epithelial cells given by RB1 LOF. Depletion of RB1 in anon-tumorigenic MCF10A cells induced reversible growth arrest (quiescence) featured by downregulation of multiple cyclins and MYC, upregulation of p27 , and lack of expression of markers which indicate cellular senescence or epithelial-mesenchymal transition (EMT). We observed a similar phenomenon in human mammary epithelial cells (HMEC) as well. Additionally, we found that RB1 depletion attenuated the activity of RAS and the downstream MAPK pathway in an RBL2/p130-dependent manner. The expression of farnesyltransferase β, which is essential for RAS maturation, was found to be downregulated following RB1 depletion also in an RBL2/p130-dependent manner. These findings unveiled an unexpected mechanism whereby normal mammary epithelial cells resist to tumor initiation upon RB1 LOF.