{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T11:32:22Z","timestamp":1767699142213,"version":"3.48.0"},"reference-count":31,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T00:00:00Z","timestamp":1767657600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Medical Research Development Fund, Tri-Service General Hospital, National Defense Medical University","award":["TSGH-C03-114036"],"award-info":[{"award-number":["TSGH-C03-114036"]}]},{"name":"Medical Research Development Fund, Tri-Service General Hospital, National Defense Medical University","award":["TSGH-C03-114037"],"award-info":[{"award-number":["TSGH-C03-114037"]}]},{"name":"Medical Research Development Fund, Tri-Service General Hospital, National Defense Medical University","award":["TSGH-C03-114038"],"award-info":[{"award-number":["TSGH-C03-114038"]}]},{"name":"Medical Research Development Fund, Tri-Service General Hospital, National Defense Medical University","award":["TSGH-D-114112"],"award-info":[{"award-number":["TSGH-D-114112"]}]},{"name":"Medical Research Development Fund, Tri-Service General Hospital, National Defense Medical University","award":["TSGH-D-112102"],"award-info":[{"award-number":["TSGH-D-112102"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Breast cancer and lung adenocarcinoma share common features, including female predominance and the expression of estrogen receptor (ER) and epidermal growth factor receptor (EGFR) during carcinogenesis. Patients with breast cancer have a significantly higher risk of developing second primary lung cancer than those without breast cancer. ER beta expression is associated with resistance to EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutant lung adenocarcinoma, indicating a potentially important interaction between ER and EGFR. However, the mechanisms underlying this crosstalk remain poorly understood. Our clinical data showed a significant correlation between antiestrogen treatment for breast cancer and mutant EGFR expression (p = 0.021) in lung adenocarcinoma patients. In vitro, tamoxifen upregulated phosphorylated EGFR (p-EGFR) in EGFR-mutant lung adenocarcinoma cell lines. Heparin-binding EGF-like growth factor was identified as a key mediator from the ER pathway that stimulates p-EGFR. Tamoxifen counteracts estrogen\u2019s effect and restores p-EGFR upregulation. Furthermore, coadministration of tamoxifen and the EGFR TKI gefitinib potentially inhibited p-EGFR expression in EGFR-mutant lung adenocarcinoma. Regular follow-up with chest computed tomography is recommended for patients with breast cancer. For those diagnosed with both ER-positive breast cancer and EGFR-mutant lung adenocarcinoma, combined tamoxifen and EGFR TKI therapy may offer an effective targeted treatment strategy.<\/jats:p>","DOI":"10.3390\/cells15020098","type":"journal-article","created":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T11:13:18Z","timestamp":1767697998000},"page":"98","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Crosstalk Mechanism of EGFR and ER in EGFR-Mutant Lung Adenocarcinoma"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3753-4877","authenticated-orcid":false,"given":"Ying-Yi","family":"Chen","sequence":"first","affiliation":[{"name":"Graduate Institute of Medical Sciences, College of Medicine, National Defense Medical University, Taipei 114202, Taiwan"},{"name":"Division of Thoracic Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical University, Taipei 114202, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei-Ting","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Dentistry, Tri-Service General Hospital, National Defense Medical University, Taipei 114202, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6704-5270","authenticated-orcid":false,"given":"Yu-Fu","family":"Su","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medical Sciences, College of Medicine, National Defense Medical University, Taipei 114202, Taiwan"},{"name":"Department of Radiation Oncology, Tri-Service General Hospital, National Defense Medical University, Taipei 114202, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi-Jen","family":"Hung","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medical Sciences, College of Medicine, National Defense Medical University, Taipei 114202, Taiwan"},{"name":"Division of Endocrinology and Metabolism, Tri-Service General Hospital, National Defense Medical University, Taipei 114202, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hao-Ai","family":"Shui","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medical Sciences, College of Medicine, National Defense Medical University, Taipei 114202, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi-Shing","family":"Shieh","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medical Sciences, College of Medicine, National Defense Medical University, Taipei 114202, Taiwan"},{"name":"Department of Dentistry, Tri-Service General Hospital, National Defense Medical University, Taipei 114202, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8741-9223","authenticated-orcid":false,"given":"Tsai-Wang","family":"Huang","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medical Sciences, College of Medicine, National Defense Medical University, Taipei 114202, Taiwan"},{"name":"Division of Thoracic Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical University, Taipei 114202, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,6]]},"reference":[{"key":"ref_1","unstructured":"(2022, December 29). Cancer Registry Annual Report, Taiwan, Available online: https:\/\/www.hpa.gov.tw\/EngPages\/List.aspx?nodeid=1061."},{"key":"ref_2","first-page":"910","article-title":"Progesterone and estrogen receptor expression and activity in human non-small cell lung cancer","volume":"76","author":"Mah","year":"2011","journal-title":"Steroids"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.critrevonc.2013.03.003","article-title":"HER2 status for prognosis and prediction of treatment efficacy in adenocarcinomas: A review","volume":"88","author":"Thibault","year":"2013","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1038\/s41419-022-04514-4","article-title":"Estrogen receptor beta promotes lung cancer invasion via increasing CXCR4 expression","volume":"13","author":"Liu","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1093\/jnci\/88.3-4.183","article-title":"Differences in lung cancer risk between men and women: Examination of the evidence","volume":"88","author":"Zang","year":"1996","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1016\/S1470-2045(01)00457-0","article-title":"Women and lung cancer: Does oestrogen play a role?","volume":"2","author":"Siegfried","year":"2001","journal-title":"Lancet Oncol."},{"key":"ref_7","first-page":"1121","article-title":"Second primary lung cancers among breast cancer patients treated with anti-estrogens have a longer cancer-specific survival","volume":"35","author":"Hsu","year":"2015","journal-title":"Anticancer Res."},{"key":"ref_8","first-page":"5871","article-title":"Surgical Resection and Outcome of Synchronous and Metachronous Primary Lung Cancer in Breast Cancer Patients","volume":"37","author":"Shoji","year":"2017","journal-title":"Anticancer Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1007\/s00432-020-03162-5","article-title":"The prognostic factors of recurrence and survival in female patients with lung adenocarcinoma and breast cancer","volume":"146","author":"Chen","year":"2020","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"325","DOI":"10.21037\/tlcr-20-513","article-title":"Hormone receptor expression correlates with EGFR gene mutation in lung cancer in patients with simultaneous primary breast cancer","volume":"9","author":"Hu","year":"2020","journal-title":"Transl. Lung Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1210\/me.2002-0368","article-title":"Bidirectional signaling between the estrogen receptor and the epidermal growth factor receptor","volume":"17","author":"Levin","year":"2003","journal-title":"Mol. Endocrinol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1158\/0008-5472.CAN-04-1872","article-title":"Combined targeting of the estrogen receptor and the epidermal growth factor receptor in non-small cell lung cancer shows enhanced antiproliferative effects","volume":"65","author":"Stabile","year":"2005","journal-title":"Cancer Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"R88","DOI":"10.1186\/bcr2158","article-title":"A candidate molecular signature associated with tamoxifen failure in primary breast cancer","volume":"10","author":"Vendrell","year":"2008","journal-title":"Breast Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.mce.2010.06.014","article-title":"Cross talk between epidermal growth factor (EGF) receptor and extra nuclear steroid receptors in cell lines","volume":"327","author":"Migliaccio","year":"2010","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1080\/14728222.2018.1502272","article-title":"Role of osteopontin as a predictive biomarker for anti-EGFR therapy in triple-negative breast cancer","volume":"22","author":"Anborgh","year":"2018","journal-title":"Expert. Opin. Ther. Targets"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e21055","DOI":"10.1016\/j.heliyon.2023.e21055","article-title":"Role of osteopontin in cancer development and treatment","volume":"9","author":"Yan","year":"2023","journal-title":"Heliyon"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"25","DOI":"10.32471\/exp-oncology.2312-8852.vol-42-no-1.14145","article-title":"Antiproliferative and apoptotic effects of anti-human HB-EGF neutralizing polyclonal antibodies in vitro","volume":"42","author":"Siromolot","year":"2020","journal-title":"Exp. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2630","DOI":"10.1002\/ijc.27926","article-title":"Reproductive and hormonal factors and the risk of lung cancer: The EAGLE study","volume":"132","author":"Pesatori","year":"2013","journal-title":"Int. J. Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4167","DOI":"10.1002\/cncr.24475","article-title":"Hormone replacement therapy and survival in lung cancer in postmenopausal women in a rural population","volume":"115","author":"Huang","year":"2009","journal-title":"Cancer"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1093\/jnci\/djq285","article-title":"Lung cancer among postmenopausal women treated with estrogen alone in the women\u2019s health initiative randomized trial","volume":"102","author":"Chlebowski","year":"2010","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Lin, F.W., Yeh, M.H., Lin, C.L., and Wei, J.C. (2022). Association between Breast Cancer and Second Primary Lung Cancer among the Female Population in Taiwan: A Nationwide Population-Based Cohort Study. Cancers, 14.","DOI":"10.3390\/cancers14122977"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.tips.2016.10.006","article-title":"Estrogen Receptor beta as a Pharmaceutical Target","volume":"38","author":"Warner","year":"2017","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1038\/s41388-018-0463-1","article-title":"Estrogen receptor \u03b2 promotes the vasculogenic mimicry (VM) and cell invasion via altering the lncRNA-MALAT1\/miR-145-5p\/NEDD9 signals in lung cancer","volume":"38","author":"Yu","year":"2019","journal-title":"Oncogene"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1158\/1078-0432.CCR-10-0992","article-title":"Combined analysis of estrogen receptor \u03b2-1 and progesterone receptor expression identifies lung cancer patients with poor outcome","volume":"17","author":"Stabile","year":"2011","journal-title":"Clin. Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"482","DOI":"10.21037\/jtd.2017.12.61","article-title":"Influence of estrogen in non-small cell lung cancer and its clinical implications","volume":"10","author":"Arrieta","year":"2018","journal-title":"J. Thorac. Dis."},{"key":"ref_26","first-page":"1313","article-title":"Estrogen receptor \u03b21 activation accelerates resistance to epidermal growth factor receptor-tyrosine kinase inhibitors in non-small cell lung cancer","volume":"39","author":"Fu","year":"2018","journal-title":"Oncol. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Zhang, L., Tian, M., Lin, J., Zhang, J., Wang, H., and Li, Z. (2020). Estrogen Receptor beta1 Expression Patterns Have Different Effects on Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors\u2019 Treatment Response in Epidermal Growth Factor Receptor Mutant Lung Adenocarcinoma. Front. Oncol., 10.","DOI":"10.3389\/fonc.2020.603883"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1097\/JTO.0b013e31824177ea","article-title":"Combining the multitargeted tyrosine kinase inhibitor vandetanib with the antiestrogen fulvestrant enhances its antitumor effect in non-small cell lung cancer","volume":"7","author":"Siegfried","year":"2012","journal-title":"J. Thorac. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"20597","DOI":"10.3390\/ijms141020597","article-title":"The epidermal growth factor receptor and its ligands in cardiovascular disease","volume":"14","author":"Makki","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.redox.2018.07.005","article-title":"Matrix metalloproteinase-2-induced epidermal growth factor receptor transactivation impairs redox balance in vascular smooth muscle cells and facilitates vascular contraction","volume":"18","author":"Prado","year":"2018","journal-title":"Redox Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5369","DOI":"10.7150\/ijbs.73949","article-title":"Tumor Microenvironment and its Implications for Antitumor Immunity in Cholangiocarcinoma: Future Perspectives for Novel Therapies","volume":"18","author":"Cao","year":"2022","journal-title":"Int. J. Biol. Sci."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/2\/98\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T11:20:48Z","timestamp":1767698448000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/2\/98"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,6]]},"references-count":31,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["cells15020098"],"URL":"https:\/\/doi.org\/10.3390\/cells15020098","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,6]]}}}