ERβ Sensitizes NSCLC to Chemotherapy by Regulating DNA Damage Response

• Published in: Molecular cancer research Vol. 16; no. 2; pp. 233 - 242
• Main Authors: Nikolos, Fotis, Thomas, Christoforos, Bado, Igor, Gustafsson, Jan-Åke
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 01.02.2018
• Subjects: Apoptosis; Breast cancer; Cancer; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Chemotherapy; CHK1 protein; Damage; Deoxyribonucleic acid; Disease control; DNA; DNA Damage; DNA Repair - drug effects; Doxorubicin; Doxorubicin - pharmacology; Estrogen Receptor beta - genetics; Estrogen Receptor beta - metabolism; Estrogen receptors; Estrogens; Etoposide; Etoposide - pharmacology; G2 Phase Cell Cycle Checkpoints - drug effects; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Humans; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Non-small cell lung carcinoma; p53 Protein; Patients; Signaling; Transcription; Transfection; Tumor Suppressor Protein p53 - genetics; Tumors; Up-Regulation
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.MCR-17-0201

The expression of wild-type estrogen receptor β (ESR2/ERβ1) correlates with clinical outcome in patients with non-small cell lung cancer (NSCLC). However, the molecular mechanism that accounts for this association is currently poorly understood. ERβ1 was previously linked to chemotherapy response in patients with breast cancer and in breast cancer cells. The effect of the receptor in NSCLC cells after chemotherapy treatment, a common remedy for advanced NSCLC, has not been studied. Here, upregulation of ERβ1 increases the sensitivity of NSCLC cells to treatment with doxorubicin and etoposide. This effect was primarily observed in p53-defecient NSCLC cells. In these cells, ERβ1 either enhanced G -M cell-cycle arrest by activating the checkpoint kinase 1 (Chk1) and altering downstream signaling or induced apoptosis. The expression of p63 target genes that control G -M checkpoint activation was altered by ERβ1 suggesting an ERβ1-p63 transcriptional cooperation in lung cancer cells that affects DNA damage response (DDR). These results suggest involvement of ERβ1 in the mechanism that regulates DNA damage response in NSCLC cells and support the potential predictive and therapeutic value of the receptor in clinical management of the disease. This study demonstrating the impact of ERβ1 on chemosensitivity of NSCLC cells suggests the predictive value of the receptor for successful response of tumors to chemotherapy and the potential benefit of chemotherapy-treated patients from the use of ER ligands. .