Expression of miRNA‐26b‐5p and its target TRPS1 is associated with radiation exposure in post‐Chernobyl breast cancer

• Published in: International journal of cancer 2018-02, Vol.142 (3), p.573-583
• Main Authors: Wilke, Christina M., Hess, Julia, Klymenko, Sergiy V., Chumak, Vadim V., Zakhartseva, Liubov M., Bakhanova, Elena V., Feuchtinger, Annette, Walch, Axel K., Selmansberger, Martin, Braselmann, Herbert, Schneider, Ludmila, Pitea, Adriana, Steinhilber, Julia, Fend, Falko, Bösmüller, Hans C., Zitzelsberger, Horst, Unger, Kristian
• Format: Article
• Language: English
• Subjects: Adult; Angiogenesis; Apoptosis; Breast cancer; Breast Neoplasms - etiology; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Cancer; Carcinogenesis; Cell adhesion & migration; Cell culture; Cell cycle; Cell migration; Chernobyl; Chernobyl Nuclear Accident; Cleanup; Deoxyribonucleic acid; DNA; DNA damage; DNA repair; DNA-Binding Proteins - biosynthesis; DNA-Binding Proteins - genetics; Exposure; Female; Gene expression; Health risk assessment; Health risks; hsa‐miR‐26b‐5p; Humans; Ionizing radiation; Medical research; MicroRNAs - biosynthesis; MicroRNAs - genetics; Middle Aged; miRNA; Mitosis; Neoplasms, Radiation-Induced - etiology; Neoplasms, Radiation-Induced - genetics; Neoplasms, Radiation-Induced - metabolism; Occupational exposure; Paraffin Embedding; radiation‐associated; Risk factors; siRNA; Tissues; Transcription; Transcription Factors - biosynthesis; Transcription Factors - genetics; TRPS1
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.31072

Ionizing radiation is a well‐recognized risk factor for the development of breast cancer. However, it is unknown whether radiation‐specific molecular oncogenic mechanisms exist. We investigated post‐Chernobyl breast cancers from radiation‐exposed female clean‐up workers and nonexposed controls for molecular changes. Radiation‐associated alterations identified in the discovery cohort (n = 38) were subsequently validated in a second cohort (n = 39). Increased expression of hsa‐miR‐26b‐5p was associated with radiation exposure in both of the cohorts. Moreover, downregulation of the TRPS1 protein, which is a transcriptional target of hsa‐miR‐26b‐5p, was associated with radiation exposure. As TRPS1 overexpression is common in sporadic breast cancer, its observed downregulation in radiation‐associated breast cancer warrants clarification of the specific functional role of TRPS1 in the radiation context. For this purpose, the impact of TRPS1 on the transcriptome was characterized in two radiation‐transformed breast cell culture models after siRNA‐knockdown. Deregulated genes upon TRPS1 knockdown were associated with DNA‐repair, cell cycle, mitosis, cell migration, angiogenesis and EMT pathways. Furthermore, we identified the interaction partners of TRPS1 from the transcriptomic correlation networks derived from gene expression data on radiation‐transformed breast cell culture models and sporadic breast cancer tissues provided by the TCGA database. The genes correlating with TRPS1 in the radiation‐transformed breast cell lines were primarily linked to DNA damage response and chromosome segregation, while the transcriptional interaction partners in the sporadic breast cancers were mostly associated with apoptosis. Thus, upregulation of hsa‐miR‐26b‐5p and downregulation of TRPS1 in radiation‐associated breast cancer tissue samples suggests these molecules representing radiation markers in breast cancer. What's new? While ionizing radiation is an established risk factor for breast cancer, little is known about mechanisms of radiation‐specific breast carcinogenesis related to low‐dose exposure. Here, investigation of molecular changes in breast cancers from female post‐Chernobyl clean‐up workers exposed to radiation revealed two radiation‐specific molecular markers: increased expression of hsa‐miR‐26b‐5p and downregulation of its target TRPS1. In human radiation‐transformed breast cells, TRPS1 knockdown was found to be associated with enrichment of DNA repair, cell cy