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

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 cell...

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Published inCancer 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
LanguageEnglish
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
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Abstract 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.
AbstractList 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 KIP1 , 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.
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 KIP1 , 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. We assessed the impact of retinoblastoma 1 (RB1) inactivation in the initiation step of mammary epithelial cells by employing nontumorigenic MCF10A cells. RB1 depletion in MCF10A cells caused growth arrest, downregulation of multiple cyclins, MAPK phosphorylation of Myc, and upregulation of p27. Furthermore, active RAS would readily transform RB‐depleted MCF10A suggesting RB acts as a barrier against excessive RAS activity by inducing quiescence.
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.
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 p27KIP1, 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.
Author Nakayama, Joji
Voon, Dominic Chih-Cheng
Kohno, Susumu
Gong, Linxiang
Takahashi, Chiaki
AuthorAffiliation 1 Division of Oncology and Molecular Biology Cancer Research Institute, Kanazawa University Kanazawa Ishikawa Japan
2 Institute for Frontier Science Initiative Kanazawa University Kanazawa Ishikawa Japan
AuthorAffiliation_xml – name: 1 Division of Oncology and Molecular Biology Cancer Research Institute, Kanazawa University Kanazawa Ishikawa Japan
– name: 2 Institute for Frontier Science Initiative Kanazawa University Kanazawa Ishikawa Japan
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  givenname: Dominic Chih-Cheng
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  surname: Voon
  fullname: Voon, Dominic Chih-Cheng
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  givenname: Joji
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  surname: Kohno
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Issue 5
Keywords RB1
RBL2/p130
quiescence
RAS
MYC
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  publication-title: Am J Transl Res
  contributor:
    fullname: Hou J
– ident: e_1_2_11_38_1
  doi: 10.1126/science.1105136
SSID ssj0036494
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Snippet 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...
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...
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StartPage 1576
SubjectTerms 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
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  providerName: ProQuest
Title RB1 loss induces quiescent state through downregulation of RAS signaling in mammary epithelial cells
URI https://www.ncbi.nlm.nih.gov/pubmed/38468443
https://www.proquest.com/docview/3054440641
https://www.proquest.com/docview/2956160194
https://pubmed.ncbi.nlm.nih.gov/PMC11093197
Volume 115
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