{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:41:32Z","timestamp":1785415292976,"version":"3.56.0"},"reference-count":29,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T00:00:00Z","timestamp":1777507200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005925","name":"Buddhist Tzu Chi Medical Foundation","doi-asserted-by":"publisher","award":["TCMF-EP 111-01, TCMF-CP 114-01"],"award-info":[{"award-number":["TCMF-EP 111-01, TCMF-CP 114-01"]}],"id":[{"id":"10.13039\/501100005925","id-type":"DOI","asserted-by":"publisher"}]},{"award":["TCMF-EP 111-01, TCMF-CP 114-01"],"award-info":[{"award-number":["TCMF-EP 111-01, TCMF-CP 114-01"]}],"id":[{"id":"https:\/\/ror.org\/04rbvc675","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Ovarian cancer remains the most lethal gynecologic malignancy, with the majority of patients presenting at advanced stages and exhibiting poor long-term survival. High-grade serous carcinoma (HGSC), the predominant subtype, likely originates from fallopian tube epithelial cells (FTECs), whose biology is strongly influenced by hormonal signaling. Progesterone receptor (PR) expression, particularly of the PR-B isoform, is associated with improved prognosis in HGSC; however, the isoform-specific molecular mechanisms in precancerous FTECs remain unclear. This study investigated the distinct biological and transcriptomic effects of PR-A and PR-B in p53- and Rb-defective FE25 FTEC-derived cells. Stable overexpression of PR-A suppressed cell proliferation, enhanced apoptosis, and induced robust senescence, whereas PR-B promoted proliferation and activated JNK\/c-Jun signaling. Upon progesterone (P4) treatment, both isoforms mediated cell-cycle arrest and apoptosis, with PR-A exhibiting stronger Sub-G1 induction. PR-A and PR-B differentially regulated cell-cycle inhibitors, senescence markers, and downstream pathways, including the PI3K\u2013Akt and MAPK pathways, while RNA sequencing analyses revealed broader P4-induced transcriptomic changes in PR-B than in PR-A, involving immune, angiogenic, and proliferative programs. Collectively, these findings demonstrate that PR-A and PR-B exert distinct yet complementary regulatory roles in FTEC biology and progesterone responsiveness. The observed PR isoform-dependent effects in FE25 cells should be interpreted as context-specific mechanistic insights rather than direct predictors of clinical prognosis or treatment response.<\/jats:p>","DOI":"10.3390\/ijms27094031","type":"journal-article","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T13:32:21Z","timestamp":1777555941000},"page":"4031","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Signaling Pathway Dissection After Progesterone Receptor Enhancement in an Immortalized Pre-Cancer Fallopian Tube Epithelial Cell Line"],"prefix":"10.3390","volume":"27","author":[{"given":"Yu-Hsun","family":"Chang","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien 970, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun-Chi","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien 970, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5105-068X","authenticated-orcid":false,"given":"Dah-Ching","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien 970, Taiwan"},{"name":"Institute of Medical Sciences, Tzu Chi University, Hualien 970, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"US Preventive Services Task Force, Grossman, D.C., Curry, S.J., Owens, D.K., Barry, M.J., Davidson, K.W., Doubeni, C.A., Epling, J.W., Kemper, A.R., and Krist, A.H. (2018). Screening for Ovarian Cancer: US Preventive Services Task Force Recommendation Statement. JAMA, 319, 588\u2013594.","DOI":"10.1001\/jama.2017.21926"},{"key":"ref_2","first-page":"284","article-title":"Ovarian Cancer Statistics, 2018","volume":"68","author":"Torre","year":"2018","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1001\/jama.2025.9495","article-title":"Ovarian Cancer: A Review","volume":"334","author":"Caruso","year":"2025","journal-title":"JAMA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.tcmj.2013.04.002","article-title":"The Fallopian Tube Is the Culprit and an Accomplice in Type II Ovarian Cancer: A Review","volume":"25","author":"Hong","year":"2013","journal-title":"Tzu Chi Med. J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3028","DOI":"10.7150\/jca.30588","article-title":"Estradiol and Progesterone Induced Differentiation and Increased Stemness Gene Expression of Human Fallopian Tube Epithelial Cells","volume":"10","author":"Chang","year":"2019","journal-title":"J. Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Chang, Y.-H., Wu, K.-C., Wang, K.-H., and Ding, D.-C. (2023). Effects of the Overexpression of Progesterone Receptors on a Precancer p53 and Rb-Defective Human Fallopian Tube Epithelial Cell Line. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241411823"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1016\/j.ygyno.2004.11.010","article-title":"Expression of Progesterone Receptor Is a Favorable Prognostic Marker in Ovarian Cancer","volume":"96","author":"Lee","year":"2005","journal-title":"Gynecol. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"36845","DOI":"10.18632\/oncotarget.15982","article-title":"Prognostic Value of Progesterone Receptor Expression in Ovarian Cancer: A Meta-Analysis","volume":"8","author":"Luo","year":"2017","journal-title":"Oncotarget"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1016\/S1470-2045(13)70253-5","article-title":"Hormone-Receptor Expression and Ovarian Cancer Survival: An Ovarian Tumor Tissue Analysis Consortium Study","volume":"14","author":"Sieh","year":"2013","journal-title":"Lancet Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Gasimli, K., Wilke, A.M., Schmeil, I., Gasimli, B., Karn, T., Becker, S., Arsenic, R., and El-Balat, A. (2025). Prognostic Impact of Estrogen and Progesterone Receptor Expression across Histological Subtypes and Clinical Factors in Epithelial Ovarian Cancer. Gynecol. Obstet. Investig., 1\u201315.","DOI":"10.1159\/000547773"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"16922","DOI":"10.1038\/s41598-017-17265-6","article-title":"The Positivity of Estrogen Receptor and Progesterone Receptor May Not Be Associated with Metastasis and Recurrence in Epithelial Ovarian Cancer","volume":"7","author":"Chen","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s13048-019-0486-4","article-title":"Progesterone Reduces Cell Survival in Primary Cultures of Endometrioid Ovarian Cancer","volume":"12","author":"Pedernera","year":"2019","journal-title":"J. Ovarian Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1111\/j.1365-2559.2011.04028.x","article-title":"Evaluation of a Hormone Receptor-Positive Ovarian Carcinoma Subtype with a Favourable Prognosis by Determination of Progesterone Receptor and Oestrogen Receptor 1 mRNA Expression in Formalin-Fixed Paraffin-Embedded Tissue","volume":"59","author":"Sinn","year":"2011","journal-title":"Histopathology"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Lenhard, M., Tereza, L., Heublein, S., Ditsch, N., Himsl, I., Mayr, D., Friese, K., and Jeschke, U. (2012). Steroid Hormone Receptor Expression in Ovarian Cancer: Progesterone Receptor B as Prognostic Marker for Patient Survival. BMC Cancer, 12.","DOI":"10.1186\/1471-2407-12-553"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Lin, H., Lan, K.-C., Ou, Y.-C., Wu, C.-H., Kang, H.-Y., Chuang, I.-C., and Fu, H.-C. (2021). Highly Expressed Progesterone Receptor B Isoform Increases Platinum Sensitivity and Survival of Ovarian High-Grade Serous Carcinoma. Cancers, 13.","DOI":"10.3390\/cancers13215578"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1488","DOI":"10.1054\/bjoc.2000.1463","article-title":"Progesterone Receptor Isoforms A and B in Human Epithelial Ovarian Carcinoma: Immunohistochemical and RT-PCR Studies","volume":"83","author":"Akahira","year":"2000","journal-title":"Br. J. Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"R31","DOI":"10.1530\/JME-14-0252","article-title":"Progesterone Action in Breast, Uterine, and Ovarian Cancers","volume":"54","author":"Diep","year":"2015","journal-title":"J. Mol. Endocrinol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e13029","DOI":"10.1111\/cpr.13029","article-title":"Cellular Models of Development of Ovarian High-Grade Serous Carcinoma: A Review of Cell of Origin and Mechanisms of Carcinogenesis","volume":"54","author":"Mei","year":"2021","journal-title":"Cell Prolif."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Chang, Y.-H., Chu, T.-Y., and Ding, D.-C. (2022). Spontaneous Transformation of a p53 and Rb-Defective Human Fallopian Tube Epithelial Cell Line after Long Passage with Features of High-Grade Serous Carcinoma. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232213843"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2557","DOI":"10.1016\/j.celrep.2017.02.049","article-title":"Progesterone Prevents High-Grade Serous Ovarian Cancer by Inducing Necroptosis of p53-Defective Fallopian Tube Epithelial Cells","volume":"18","author":"Wu","year":"2017","journal-title":"Cell Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1929","DOI":"10.1210\/clinem\/dgab195","article-title":"Progesterone Receptors Promote Quiescence & Ovarian Cancer Cell Phenotypes via DREAM in p53-Mutant Fallopian Tube Models","volume":"106","author":"Mauro","year":"2021","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1158\/1541-7786.MCR-15-0431","article-title":"Active FOXO1 Is a Key Determinant of Isoform-Specific Progesterone Receptor Transactivation and Senescence Programming","volume":"14","author":"Diep","year":"2016","journal-title":"Mol. Cancer Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5650","DOI":"10.1210\/en.2003-0484","article-title":"Distinct Molecular Pathways Mediate Progesterone-Induced Growth Inhibition and Focal Adhesion","volume":"144","author":"Lin","year":"2003","journal-title":"Endocrinology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.4161\/cc.24550","article-title":"Progesterone Receptors Induce FOXO1-Dependent Senescence in Ovarian Cancer Cells","volume":"12","author":"Diep","year":"2013","journal-title":"Cell Cycle"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"eaaz9646","DOI":"10.1126\/scisignal.aaz9646","article-title":"Constitutive Expression of Progesterone Receptor Isoforms Promotes the Development of Hormone-Dependent Ovarian Neoplasms","volume":"13","author":"Wetendorf","year":"2020","journal-title":"Sci. Signal."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.mce.2011.09.017","article-title":"Role of Phosphorylation in Progesterone Receptor Signaling and Specificity","volume":"357","author":"Hagan","year":"2012","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"C281","DOI":"10.1152\/ajpcell.00422.2003","article-title":"G1 Cell Cycle Progression and the Expression of G1 Cyclins Are Regulated by PI3K\/AKT\/mTOR\/p70S6K1 Signaling in Human Ovarian Cancer Cells","volume":"287","author":"Gao","year":"2004","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1091\/mbc.e12-11-0807","article-title":"Progesterone Receptor Isoforms PRA and PRB Differentially Contribute to Breast Cancer Cell Migration through Interaction with Focal Adhesion Kinase Complexes","volume":"24","author":"Bellance","year":"2013","journal-title":"Mol. Biol. Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"8926","DOI":"10.1093\/nar\/gkt706","article-title":"A Common Docking Domain in Progesterone Receptor-B Links DUSP6 and CK2 Signaling to Proliferative Transcriptional Programs in Breast Cancer Cells","volume":"41","author":"Hagan","year":"2013","journal-title":"Nucleic Acids Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/9\/4031\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T04:10:36Z","timestamp":1778472636000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/9\/4031"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,30]]},"references-count":29,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["ijms27094031"],"URL":"https:\/\/doi.org\/10.3390\/ijms27094031","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,30]]}}}