CBFB cooperates with p53 to maintain TAp73 expression and suppress breast cancer
| Autor: | Gamze Ayaz, Howard H. Yang, Young-Im Kim, Yu-Chou Tseng, Maxwell P. Lee, Navdeep Malik, Jing Huang, Wendy Dubois, Hualong Yan, Shunlin Jiang, Chengyu Liu |
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| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
Transcription Genetic Carcinogenesis QH426-470 medicine.disease_cause Suppressor Genes Lung and Intrathoracic Tumors law.invention Prostate cancer Mice 0302 clinical medicine law Breast Tumors Medicine and Health Sciences Genes Tumor Suppressor Receptor Notch3 Genetics (clinical) Regulation of gene expression 0303 health sciences Mutation Prostate Cancer Luciferase Assay Prostate Diseases Immunohistochemistry Gene Expression Regulation Neoplastic Cell Transformation Neoplastic Bioassays and Physiological Analysis Oncology 030220 oncology & carcinogenesis Core Binding Factor Alpha 2 Subunit Female Research Article Tumor Suppressor Genes Urology Breast Neoplasms Biology Research and Analysis Methods Core Binding Factor beta Subunit 03 medical and health sciences Breast cancer Gene Types Cell Line Tumor Breast Cancer medicine Genetics Animals Humans Molecular Biology Ecology Evolution Behavior and Systematics 030304 developmental biology Cell Proliferation Enzyme Assays Cell growth Cancer Cancers and Neoplasms Biology and Life Sciences Tumor Protein p73 medicine.disease Xenograft Model Antitumor Assays Genitourinary Tract Tumors Cancer research Suppressor Tumor Suppressor Protein p53 Biochemical Analysis |
| Zdroj: | PLoS Genetics PLoS Genetics, Vol 17, Iss 5, p e1009553 (2021) |
| ISSN: | 1553-7404 |
| Popis: | The CBFB gene is frequently mutated in several types of solid tumors. Emerging evidence suggests that CBFB is a tumor suppressor in breast cancer. However, our understanding of the tumor suppressive function of CBFB remains incomplete. Here, we analyze genetic interactions between mutations of CBFB and other highly mutated genes in human breast cancer datasets and find that CBFB and TP53 mutations are mutually exclusive, suggesting a functional association between CBFB and p53. Integrated genomic studies reveal that TAp73 is a common transcriptional target of CBFB and p53. CBFB cooperates with p53 to maintain TAp73 expression, as either CBFB or p53 loss leads to TAp73 depletion. TAp73 re-expression abrogates the tumorigenic effect of CBFB deletion. Although TAp73 loss alone is insufficient for tumorigenesis, it enhances the tumorigenic effect of NOTCH3 overexpression, a downstream event of CBFB loss. Immunohistochemistry shows that p73 loss is coupled with higher proliferation in xenografts. Moreover, TAp73 loss-of-expression is a frequent event in human breast cancer tumors and cell lines. Together, our results significantly advance our understanding of the tumor suppressive functions of CBFB and reveal a mechanism underlying the communication between the two tumor suppressors CBFB and p53. Author summary The success of precision medicine in oncology requires a detailed understanding of genetic alterations and the functional associations between them. Recent genome-wide sequencing studies found that breast, ovarian, and prostate tumors have frequent CBFB mutations. Emerging evidence suggests that CBFB is a tumor suppressor in breast tumors. However, our understanding of the tumor suppressive functions of CBFB remains fragmented. In this study, our genetic analyses of CBFB and TP53 mutations suggest that CBFB and p53 are functionally associated in breast tumors. By leveraging the rich knowledge of the tumor suppressive function of p53, we found that CBFB induces the expression of TAp73, a well-established mediator for the tumor suppressive function of p53. TAp73 re-expression inhibits the tumorigenicity of CBFB-deficient breast cells. In addition, TAp73 depletion drives breast tumorigenesis by cooperating with NOTCH3, a CBFB-repressed oncogene. Moreover, human breast tumors and cancer cell lines frequently lose the expression of TAp73. Together, our study gains a mechanistic understanding of the tumor suppressive functions of CBFB, reveals a functional association between CBFB and p53 in breast cancer, and has important implications in precision medicine for breast cancer. |
| Databáze: | OpenAIRE |
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