{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T19:33:36Z","timestamp":1778873616610,"version":"3.51.4"},"reference-count":80,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2024,3,9]],"date-time":"2024-03-09T00:00:00Z","timestamp":1709942400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"UNAM-PAPIIT","award":["IN208423"],"award-info":[{"award-number":["IN208423"]}]},{"name":"UNAM-PAPIIT","award":["IN208520"],"award-info":[{"award-number":["IN208520"]}]},{"name":"UNAM-PAPIIT","award":["256994"],"award-info":[{"award-number":["256994"]}]},{"DOI":"10.13039\/501100003141","name":"Consejo Nacional de Humanidades, Ciencias y Tecnolog\u00edas (CONAHCYT), M\u00e9xico","doi-asserted-by":"publisher","award":["IN208423"],"award-info":[{"award-number":["IN208423"]}],"id":[{"id":"10.13039\/501100003141","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003141","name":"Consejo Nacional de Humanidades, Ciencias y Tecnolog\u00edas (CONAHCYT), M\u00e9xico","doi-asserted-by":"publisher","award":["IN208520"],"award-info":[{"award-number":["IN208520"]}],"id":[{"id":"10.13039\/501100003141","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003141","name":"Consejo Nacional de Humanidades, Ciencias y Tecnolog\u00edas (CONAHCYT), M\u00e9xico","doi-asserted-by":"publisher","award":["256994"],"award-info":[{"award-number":["256994"]}],"id":[{"id":"10.13039\/501100003141","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>HER2-positive breast cancer is associated with aggressive behavior and reduced survival rates. Calcitriol restores the antiproliferative activity of antiestrogens in estrogen receptor (ER)-negative breast cancer cells by re-expressing ER\u03b1. Furthermore, calcitriol and its analog, EB1089, enhance responses to standard anti-cancer drugs. Therefore, we aimed to investigate EB1089 effects when added to the combined treatment of lapatinib and antiestrogens on the proliferation of HER2-positive breast cancer cells. BT-474 (ER-positive\/HER2-positive) and SK-BR-3 (ER-negative\/HER2-positive) cells were pre-treated with EB1089 to modulate ER expression. Then, cells were treated with EB1089 in the presence of lapatinib with or without the antiestrogens, and proliferation, phosphorylation array assays, and Western blot analysis were performed. The results showed that EB1089 restored the antiproliferative response to antiestrogens in SK-BR-3 cells and improved the inhibitory effects of the combination of lapatinib with antiestrogens in the two cell lines. Moreover, EB1089, alone or combined, modulated ER\u03b1 protein expression and reduced Akt phosphorylation in HER2-positive cells. EB1089 significantly enhanced the cell growth inhibitory effect of lapatinib combined with antiestrogens in HER2-positive breast cancer cells by modulating ER\u03b1 expression and Akt phosphorylation suppression. These results highlight the potential of this therapeutic approach as a promising strategy for managing HER2-positive breast cancer.<\/jats:p>","DOI":"10.3390\/ijms25063165","type":"journal-article","created":{"date-parts":[[2024,3,11]],"date-time":"2024-03-11T06:05:30Z","timestamp":1710137130000},"page":"3165","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["EB1089 Increases the Antiproliferative Response of Lapatinib in Combination with Antiestrogens in HER2-Positive Breast Cancer Cells"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3547-6602","authenticated-orcid":false,"given":"Ang\u00e8le Sorel","family":"Achounna","sequence":"first","affiliation":[{"name":"Departamento de Biolog\u00eda Molecular y Biotecnolog\u00eda, Instituto de Investigaciones Biom\u00e9dicas, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Ciudad de M\u00e9xico 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2044-4584","authenticated-orcid":false,"given":"David","family":"Ordaz-Rosado","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda de la Reproducci\u00f3n Dr. Carlos Gual Castro, Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n, Vasco de Quiroga No. 15, Belisario Dom\u00ednguez Secci\u00f3n XVI, Tlalpan, Ciudad de M\u00e9xico 14080, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3311-2258","authenticated-orcid":false,"given":"Janice","family":"Garc\u00eda-Quiroz","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda de la Reproducci\u00f3n Dr. Carlos Gual Castro, Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n, Vasco de Quiroga No. 15, Belisario Dom\u00ednguez Secci\u00f3n XVI, Tlalpan, Ciudad de M\u00e9xico 14080, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4030-6616","authenticated-orcid":false,"given":"Gabriela","family":"Morales-Guadarrama","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda de la Reproducci\u00f3n Dr. Carlos Gual Castro, Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n, Vasco de Quiroga No. 15, Belisario Dom\u00ednguez Secci\u00f3n XVI, Tlalpan, Ciudad de M\u00e9xico 14080, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edgar","family":"Milo-Rocha","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda Molecular y Biotecnolog\u00eda, Instituto de Investigaciones Biom\u00e9dicas, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Ciudad de M\u00e9xico 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4431-969X","authenticated-orcid":false,"given":"Fernando","family":"Larrea","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda de la Reproducci\u00f3n Dr. Carlos Gual Castro, Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n, Vasco de Quiroga No. 15, Belisario Dom\u00ednguez Secci\u00f3n XVI, Tlalpan, Ciudad de M\u00e9xico 14080, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5947-4222","authenticated-orcid":false,"given":"Lorenza","family":"D\u00edaz","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda de la Reproducci\u00f3n Dr. Carlos Gual Castro, Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n, Vasco de Quiroga No. 15, Belisario Dom\u00ednguez Secci\u00f3n XVI, Tlalpan, Ciudad de M\u00e9xico 14080, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2482-3963","authenticated-orcid":false,"given":"Roc\u00edo","family":"Garc\u00eda-Becerra","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda Molecular y Biotecnolog\u00eda, Instituto de Investigaciones Biom\u00e9dicas, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Ciudad de M\u00e9xico 04510, Mexico"},{"name":"Programa de Investigaci\u00f3n de C\u00e1ncer de Mama, Instituto de Investigaciones Biom\u00e9dicas, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Ciudad de M\u00e9xico 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.breast.2022.08.010","article-title":"Current and future burden of breast cancer: Global statistics for 2020 and 2040","volume":"66","author":"Arnold","year":"2022","journal-title":"Breast"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Haibe-Kains, B., Desmedt, C., Piette, F., Buyse, M., Cardoso, F., Van\u2019t Veer, L., Piccart, M., Bontempi, G., and Sotiriou, C. (2008). Comparison of prognostic gene expression signatures for breast cancer. BMC Genom., 9.","DOI":"10.1186\/1471-2164-9-394"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1016\/S1470-2045(14)70080-4","article-title":"Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (NOAH): Follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort","volume":"15","author":"Gianni","year":"2014","journal-title":"Lancet Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"6255","DOI":"10.1038\/sj.onc.1205794","article-title":"Anti-tumor activity of GW572016: A dual tyrosine kinase inhibitor blocks EGF activation of EGFR\/erbB2 and downstream Erk1\/2 and AKT pathways","volume":"21","author":"Xia","year":"2002","journal-title":"Oncogene"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1159\/000528756","article-title":"Current Standards and Future Outlooks in Metastatic Her2-Positive Breast Cancer","volume":"18","author":"Suppan","year":"2023","journal-title":"Breast Care"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1178223420945694","DOI":"10.1177\/1178223420945694","article-title":"Endocrine Therapy Plus Anti-HER2 Therapy as Adjuvant Systemic Therapy for Luminal HER2-Positive Breast Cancer: An Analysis of the National Cancer Database","volume":"14","author":"Nahleh","year":"2020","journal-title":"Breast Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.critrevonc.2015.02.002","article-title":"HER2-positive metastatic breast cancer: A changing scenario","volume":"95","author":"Mustacchi","year":"2015","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"101","DOI":"10.7150\/jca.1.101","article-title":"Vitamin D in combination cancer treatment","volume":"1","author":"Ma","year":"2010","journal-title":"J. Cancer"},{"key":"ref_9","first-page":"1486","article-title":"The addition of calcitriol or its synthetic analog EB1089 to lapatinib and neratinib treatment inhibits cell growth and promotes apoptosis in breast cancer cells","volume":"7","author":"Diaz","year":"2017","journal-title":"Am. J. Cancer Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.jsbmb.2014.12.006","article-title":"Calcitriol and its analogues enhance the antiproliferative activity of gefitinib in breast cancer cells","volume":"148","author":"Diaz","year":"2015","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Segovia-Mendoza, M., Garcia-Quiroz, J., Diaz, L., and Garcia-Becerra, R. (2021). Combinations of Calcitriol with Anticancer Treatments for Breast Cancer: An Update. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222312741"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Santos-Martinez, N., Diaz, L., Ordaz-Rosado, D., Garcia-Quiroz, J., Barrera, D., Avila, E., Halhali, A., Medina-Franco, H., Ibarra-Sanchez, M.J., and Esparza-Lopez, J. (2014). Calcitriol restores antiestrogen responsiveness in estrogen receptor negative breast cancer cells: A potential new therapeutic approach. BMC Cancer, 14.","DOI":"10.1186\/1471-2407-14-230"},{"key":"ref_13","first-page":"5951","article-title":"Calcitriol induces estrogen receptor alpha expression through direct transcriptional regulation and epigenetic modifications in estrogen receptor-negative breast cancer cells","volume":"11","author":"Diaz","year":"2021","journal-title":"Am. J. Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2273","DOI":"10.1016\/0006-2952(92)90669-A","article-title":"EB1089: A new vitamin D analogue that inhibits the growth of breast cancer cells in vivo and in vitro","volume":"44","author":"Colston","year":"1992","journal-title":"Biochem. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1016\/S0006-2952(96)00816-7","article-title":"Metabolism of the vitamin D analog EB 1089: Identification of in vivo and in vitro liver metabolites and their biological activities","volume":"53","author":"Kissmeyer","year":"1997","journal-title":"Biochem. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1016\/0006-2952(95)02242-2","article-title":"A novel vitamin D analog with two double bonds in its side chain. A potent inducer of osteoblastic cell differentiation","volume":"51","author":"Mahonen","year":"1996","journal-title":"Biochem. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/0960-0760(95)00218-9","article-title":"Differential effects of 1,25-dihydroxyvitamin D3-analogs on osteoblast-like cells and on in vitro bone resorption","volume":"55","author":"Pols","year":"1995","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1530\/ERC-12-0281","article-title":"Transrepression of the estrogen receptor promoter by calcitriol in human breast cancer cells via two negative vitamin D response elements","volume":"20","author":"Swami","year":"2013","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_19","first-page":"3371","article-title":"1alpha,25-Dihydroxyvitamin D3 down-regulates estrogen receptor abundance and suppresses estrogen actions in MCF-7 human breast cancer cells","volume":"6","author":"Swami","year":"2000","journal-title":"Clin. Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1677\/joe.0.1410555","article-title":"Effects of a new synthetic vitamin D analogue, EB1089, on the oestrogen-responsive growth of human breast cancer cells","volume":"141","author":"James","year":"1994","journal-title":"J. Endocrinol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1054\/bjoc.2000.1646","article-title":"Anti-oestrogen resistant human breast cancer cell lines are more sensitive towards treatment with the vitamin D analogue EB1089 than parent MCF-7 cells","volume":"84","author":"Larsen","year":"2001","journal-title":"Br. J. Cancer"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1158\/1535-7163.MCT-05-0399","article-title":"Delineation of molecular mechanisms of sensitivity to lapatinib in breast cancer cell lines using global gene expression profiles","volume":"6","author":"Hegde","year":"2007","journal-title":"Mol. Cancer Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"R121","DOI":"10.1186\/bcr3067","article-title":"Different mechanisms for resistance to trastuzumab versus lapatinib in HER2-positive breast cancers--role of estrogen receptor and HER2 reactivation","volume":"13","author":"Wang","year":"2011","journal-title":"Breast Cancer Res."},{"key":"ref_24","first-page":"2789","article-title":"Antiestrogen potentiation of antiproliferative effects of vitamin D3 analogues in breast cancer cells","volume":"56","author":"Gibson","year":"1996","journal-title":"Cancer Res."},{"key":"ref_25","first-page":"220","article-title":"The role of oestrogen and progesterone receptors in breast cancer\u2014Immunohistochemical evaluation of oestrogen and progesterone receptor expression in invasive breast cancer in women","volume":"19","author":"Patera","year":"2015","journal-title":"Contemp. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1038\/nrc1362","article-title":"The TOR pathway: A target for cancer therapy","volume":"4","author":"Bjornsti","year":"2004","journal-title":"Nat. Rev. Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1038\/nrc839","article-title":"The phosphatidylinositol 3-Kinase AKT pathway in human cancer","volume":"2","author":"Vivanco","year":"2002","journal-title":"Nat. Rev. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"40057","DOI":"10.1074\/jbc.M303621200","article-title":"Src family protein-tyrosine kinases alter the function of PTEN to regulate phosphatidylinositol 3-kinase\/AKT cascades","volume":"278","author":"Lu","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1146\/annurev-med-042513-015127","article-title":"Targeting HER2 for the treatment of breast cancer","volume":"66","author":"Rimawi","year":"2015","journal-title":"Annu. Rev. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1111\/1759-7714.12239","article-title":"Activated estrogen receptor-mitogen-activated protein kinases cross talk confer acquired resistance to lapatinib","volume":"6","author":"Li","year":"2015","journal-title":"Thorac. Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1593\/tlo.11127","article-title":"Simultaneous Inhibition of Estrogen Receptor and the HER2 Pathway in Breast Cancer: Effects of HER2 Abundance","volume":"4","author":"Emde","year":"2011","journal-title":"Transl. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/j.jsbmb.2010.02.009","article-title":"Vitamin D and breast cancer: Inhibition of estrogen synthesis and signaling","volume":"121","author":"Krishnan","year":"2010","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e10582","DOI":"10.1002\/jbm4.10582","article-title":"Vitamin D and Breast Cancer: Mechanistic Update","volume":"5","author":"Welsh","year":"2021","journal-title":"JBMR Plus"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5020","DOI":"10.3390\/nu7065020","article-title":"Mechanistic Effects of Calcitriol in Cancer Biology","volume":"7","author":"Diaz","year":"2015","journal-title":"Nutrients"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/0960-0760(93)90226-M","article-title":"EB 1089, a novel vitamin D analogue, has strong antiproliferative and differentiation inducing effects on cancer cells","volume":"46","author":"Mathiasen","year":"1993","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1023\/B:BREA.0000021047.37869.95","article-title":"Sequential versus combined treatment of human breast cancer cells with antiestrogens and the vitamin D analogue EB1089 and evaluation of predictive markers for vitamin D treatment","volume":"85","author":"Christensen","year":"2004","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_37","first-page":"2350","article-title":"The combination of a potent vitamin D3 analog, EB 1089, with ionizing radiation reduces tumor growth and induces apoptosis of MCF-7 breast tumor xenografts in nude mice","volume":"9","author":"Sundaram","year":"2003","journal-title":"Clin. Cancer Res."},{"key":"ref_38","first-page":"5711","article-title":"Inhibition of breast cancer cell growth by combined treatment with vitamin D3 analogues and tamoxifen","volume":"54","author":"Pols","year":"1994","journal-title":"Cancer Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1007\/s00394-015-0930-1","article-title":"Sensitization of estrogen receptor-positive breast cancer cell lines to 4-hydroxytamoxifen by isothiocyanates present in cruciferous plants","volume":"55","author":"Pawlik","year":"2016","journal-title":"Eur. J. Nutr."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"7795","DOI":"10.1073\/pnas.0602468103","article-title":"A model of acquired autoresistance to a potent ErbB2 tyrosine kinase inhibitor and a therapeutic strategy to prevent its onset in breast cancer","volume":"103","author":"Xia","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","first-page":"6384278","article-title":"Calcitriol Inhibits the Proliferation of Triple-Negative Breast Cancer Cells through a Mechanism Involving the Proinflammatory Cytokines IL-1beta and TNF-alpha","volume":"2019","author":"Diaz","year":"2019","journal-title":"J. Immunol. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/S0960-0760(03)00028-1","article-title":"Efficacy of Vitamin D compounds to modulate estrogen receptor negative breast cancer growth and invasion","volume":"84","author":"Flanagan","year":"2003","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_43","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_44","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1210\/er.2006-0045","article-title":"Crosstalk between the estrogen receptor and the HER tyrosine kinase receptor family: Molecular mechanism and clinical implications for endocrine therapy resistance","volume":"29","author":"Arpino","year":"2008","journal-title":"Endocr. Rev."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1007\/s00280-009-1190-7","article-title":"Patterns of relapse and metastatic spread in HER2-overexpressing breast cancer according to estrogen receptor status","volume":"66","author":"Park","year":"2010","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_46","first-page":"20","article-title":"Steroid receptors and other prognostic factors in primary breast cancer","volume":"15","author":"Clark","year":"1988","journal-title":"Semin. Oncol."},{"key":"ref_47","first-page":"E99","article-title":"Steroid hormone receptors and carcinoma of the breast","volume":"243","author":"McGuire","year":"1982","journal-title":"Am. J. Physiol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1309\/4WV79N2GHJ3X1841","article-title":"Immunohistochemistry of estrogen and progesterone receptors reconsidered: Experience with 5993 breast cancers","volume":"123","author":"Nadji","year":"2005","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1007\/s10549-010-1024-7","article-title":"Combined Src and ER blockade impairs human breast cancer proliferation in vitro and in vivo","volume":"128","author":"Chen","year":"2011","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1007\/BF01807034","article-title":"Effects of short-term antiestrogen treatment of primary breast cancer on estrogen receptor mRNA and protein expression and on estrogen-regulated genes","volume":"41","author":"McClelland","year":"1996","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_51","first-page":"5312","article-title":"Up-regulation of estrogen receptors by nonsteroidal antiestrogens in human breast cancer","volume":"49","author":"Kiang","year":"1989","journal-title":"Cancer Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1002\/1097-0142(19930215)71:4<1266::AID-CNCR2820710416>3.0.CO;2-K","article-title":"Up-regulation of estrogen receptor by tamoxifen in human breast cancer","volume":"71","author":"Noguchi","year":"1993","journal-title":"Cancer"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"21762","DOI":"10.1038\/s41598-020-78646-y","article-title":"Combination treatment with a PI3K\/Akt\/mTOR pathway inhibitor overcomes resistance to anti-HER2 therapy in PIK3CA-mutant HER2-positive breast cancer cells","volume":"10","author":"Fujimoto","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1744","DOI":"10.1016\/j.molonc.2015.05.008","article-title":"Tamoxifen induces a pluripotency signature in breast cancer cells and human tumors","volume":"9","author":"Notas","year":"2015","journal-title":"Mol. Oncol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"7029","DOI":"10.1158\/1078-0432.CCR-07-0587","article-title":"Reversal of the estrogen receptor negative phenotype in breast cancer and restoration of antiestrogen response","volume":"13","author":"Bayliss","year":"2007","journal-title":"Clin. Cancer Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"427","DOI":"10.2147\/OTT.S76116","article-title":"Andrographolide inhibits hypoxia-inducible factor-1 through phosphatidylinositol 3-kinase\/AKT pathway and suppresses breast cancer growth","volume":"8","author":"Li","year":"2015","journal-title":"Onco Targets Ther."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"She, Q.B., Gruvberger-Saal, S.K., Maurer, M., Chen, Y., Jumppanen, M., Su, T., Dendy, M., Lau, Y.K., Memeo, L., and Horlings, H.M. (2016). Integrated molecular pathway analysis informs a synergistic combination therapy targeting PTEN\/PI3K and EGFR pathways for basal-like breast cancer. BMC Cancer, 16.","DOI":"10.1186\/s12885-016-2609-2"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/j.bbcan.2019.03.003","article-title":"Targeting PI3K signaling in cancer: Challenges and advances","volume":"1871","author":"Gulluni","year":"2019","journal-title":"Biochim. Biophys. Acta Rev. Cancer"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1186\/bcr3039","article-title":"Mutations in the phosphatidylinositol 3-kinase pathway: Role in tumor progression and therapeutic implications in breast cancer","volume":"13","author":"Miller","year":"2011","journal-title":"Breast Cancer Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1080\/15384047.2014.1002693","article-title":"PI3K-independent mTOR activation promotes lapatinib resistance and IAP expression that can be effectively reversed by mTOR and Hsp90 inhibition","volume":"16","author":"Brady","year":"2015","journal-title":"Cancer Biol. Ther."},{"key":"ref_61","first-page":"4164","article-title":"Combination of 1alpha,25-dihydroxyvitamin D(3) with dexamethasone enhances cell cycle arrest and apoptosis: Role of nuclear receptor cross-talk and Erk\/Akt signaling","volume":"7","author":"Bernardi","year":"2001","journal-title":"Clin. Cancer Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"26365","DOI":"10.1074\/jbc.M010101200","article-title":"Vitamin D(3)-induced apoptosis of murine squamous cell carcinoma cells. Selective induction of caspase-dependent MEK cleavage and up-regulation of MEKK-1","volume":"276","author":"McGuire","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"8266","DOI":"10.1158\/0008-5472.CAN-05-4045","article-title":"Mechanisms of tumor regression and resistance to estrogen deprivation and fulvestrant in a model of estrogen receptor-positive, HER-2\/neu-positive breast cancer","volume":"66","author":"Massarweh","year":"2006","journal-title":"Cancer Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"R29","DOI":"10.1186\/bcr2848","article-title":"Fulvestrant-induced expression of ErbB3 and ErbB4 receptors sensitizes oestrogen receptor-positive breast cancer cells to heregulin beta1","volume":"13","author":"Hutcheson","year":"2011","journal-title":"Breast Cancer Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"6594","DOI":"10.1046\/j.1432-1327.2000.01753.x","article-title":"Transcription inhibitors stimulate translation of 5\u2032 TOP mRNAs through activation of S6 kinase and the mTOR\/FRAP signalling pathway","volume":"267","author":"Loreni","year":"2000","journal-title":"Eur. J. Biochem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"3693","DOI":"10.1093\/emboj\/16.12.3693","article-title":"Rapamycin suppresses 5\u2032TOP mRNA translation through inhibition of p70s6k","volume":"16","author":"Jefferies","year":"1997","journal-title":"Embo J."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"4990","DOI":"10.1128\/MCB.15.9.4990","article-title":"The translation initiation factor eIF-4E binds to a common motif shared by the translation factor eIF-4 gamma and the translational repressors 4E-binding proteins","volume":"15","author":"Mader","year":"1995","journal-title":"Mol. Cell Biol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"5450","DOI":"10.1128\/MCB.16.10.5450","article-title":"Cap-binding protein (eukaryotic initiation factor 4E) and 4E-inactivating protein BP-1 independently regulate cap-dependent translation","volume":"16","author":"Feigenblum","year":"1996","journal-title":"Mol. Cell Biol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"3928","DOI":"10.1016\/j.febslet.2013.10.043","article-title":"Eukaryotic translation initiation is controlled by cooperativity effects within ternary complexes of 4E-BP1, eIF4E, and the mRNA 5\u2032 cap","volume":"587","author":"Gorka","year":"2013","journal-title":"FEBS Lett."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.3892\/ijmm.2015.2091","article-title":"BAD-mediated apoptotic pathway is associated with human cancer development","volume":"35","author":"Stickles","year":"2015","journal-title":"Int. J. Mol. Med."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.gde.2010.12.001","article-title":"Apoptosis and oncogenesis: Give and take in the BCL-2 family","volume":"21","author":"Llambi","year":"2011","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"32149","DOI":"10.18632\/oncotarget.24605","article-title":"Identification of key pathways and genes in response to trastuzumab treatment in breast cancer using bioinformatics analysis","volume":"9","author":"Zeng","year":"2018","journal-title":"Oncotarget"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1038\/35096075","article-title":"The renaissance of GSK3","volume":"2","author":"Cohen","year":"2001","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/bj3590001","article-title":"GSK3 takes centre stage more than 20 years after its discovery","volume":"359","author":"Frame","year":"2001","journal-title":"Biochem. J."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1146\/annurev.cellbio.13.1.513","article-title":"Cellular functions regulated by Src family kinases","volume":"13","author":"Thomas","year":"1997","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1038\/bjc.2014.327","article-title":"Src, a potential target for overcoming trastuzumab resistance in HER2-positive breast carcinoma","volume":"111","author":"Peiro","year":"2014","journal-title":"Br. J. Cancer"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1352","DOI":"10.1158\/0008-5472.CAN-06-1020","article-title":"Long-term treatment with tamoxifen facilitates translocation of estrogen receptor alpha out of the nucleus and enhances its interaction with EGFR in MCF-7 breast cancer cells","volume":"67","author":"Fan","year":"2007","journal-title":"Cancer Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1677\/erc.1.00946","article-title":"Antiestrogen-resistant human breast cancer cells require activated protein kinase B\/Akt for growth","volume":"12","author":"Frogne","year":"2005","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1111\/cas.13238","article-title":"HSP90 inhibitor AUY922 can reverse Fulvestrant induced feedback reaction in human breast cancer cells","volume":"108","author":"Bai","year":"2017","journal-title":"Cancer Sci."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"3131","DOI":"10.7150\/jca.18457","article-title":"Breast Cancer Cell Line Classification and Its Relevance with Breast Tumor Subtyping","volume":"8","author":"Dai","year":"2017","journal-title":"J. Cancer"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/6\/3165\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:11:20Z","timestamp":1760105480000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/6\/3165"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,9]]},"references-count":80,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2024,3]]}},"alternative-id":["ijms25063165"],"URL":"https:\/\/doi.org\/10.3390\/ijms25063165","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,9]]}}}