dc.contributor.advisor | Peterson-Peguero, Esther A | |
dc.contributor.author | Rodriguez-Martir, Keishla M | |
dc.date.accessioned | 2022-06-29T21:46:11Z | |
dc.date.available | 2022-06-29T21:46:11Z | |
dc.date.issued | 2022-05-25 | |
dc.identifier.uri | https://hdl.handle.net/11721/2854 | |
dc.description.abstract | Coumestrol (Cou) is a phytoestrogen present in soy and clover sprouts which is structurally similar to estrogen (E2) and has a cytotoxic effect in breast cancer cell lines. Nevertheless, the molecular mechanism by which Cou can exert its effect in the most aggressive breast cancer subtype, triple-negative inflammatory breast cancer (TN-IBC), is still unknown. Studies show that TN-IBC cell lines are unresponsive to hormonal therapies, but E2 can activate signaling pathways involved in pro-oncogenic phenotypes such as motility and invasion by activating a rapid estrogen-dependent non-genomic signaling. Therefore, the objective of this study was to determine the anti-cancer effect of Cou in TN-IBC cell lines (using 2D and 3D culture models) and the molecular mechanism Cou exerts for its anti-cancer activity. Dose-response curves of Cou in 2D and 3D culture models of TN-IBC cell lines were generated to determine the half-maximal inhibitory concentration (IC<sub>50</sub>). Relative cell viability was measured in ER-positive, triple-negative, TN-IBC, and HER2-amplified IBC cell lines. Functional assays were performed in TN-IBC cell lines to determine the effect of E2, Cou, and E2/Cou combination treatments on cell viability, migration, invasion, proliferation, and tumor emboli growth. Additionally, the effect of Cou and E2 treatments on phosphorylation of downstream kinases was analyzed by a proteome profile human phospho-kinase array. RNA-seq was performed in TN-IBC cell lines to identify transcriptome changes after Cou treatment. Our data demonstrated that Cou treatment using the IC<sub>50</sub> (13µM in 2D models and 50µM in 3D models) decreased cell viability in TN-IBC cell lines. Similarly, Cou treatment reduces triple-negative non-IBC cell viability. In comparison with E2, Cou decreases migration, invasion, proliferation, and tumor emboli growth in TN-IBC cell lines. Finally, Cou treatment reduces the phosphorylation of kinases MAPK/ERK and PI3K/AKT that promote pro-oncogenic phenotypes and upregulate genes such as TIPARP, recently involved in breast cancer phenotype suppression. In summary, this study guide us in elucidating a signaling pathway affected by Cou’s anti-cancer activity. More importantly, it opens the opportunities to design more effective targeted therapeutic strategies to improve the prognosis and survival rates of IBC patients. | en_US |
dc.description.sponsorship | This project is supported by UPR Fondos Institucionales para la Investigación (FIPI to E. Peterson), NIH 1R21CA253609-01 and RISE program (5R25GM061151-20). | en_US |
dc.language.iso | en_US | en_US |
dc.rights | Attribution-NonCommercial-NoDerivs 3.0 United States | * |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/us/ | * |
dc.subject | Anticancer agent | en_US |
dc.subject | Estrogen non-genomic signaling pathway | en_US |
dc.subject | Inflammatory breast cáncer (IBC) | en_US |
dc.subject.lcsh | Breast--Cancer | en_US |
dc.subject.lcsh | Cancer--Treatment | en_US |
dc.subject.lcsh | Coumestrol | en_US |
dc.subject.lcsh | Inflammatory disease and therapy | en_US |
dc.subject.lcsh | Phytoestrogens | en_US |
dc.title | Phytoestrogen coumestrol as an anti-cancer therapy against triple-negative inflammatory breast cancer | en_US |
dc.type | Dissertation | en_US |
dc.rights.holder | © 2022 Keishla M. Rodriguez-Martir | en_US |
dc.contributor.committee | Zayas, Beatriz | |
dc.contributor.committee | Vivas, Pablo | |
dc.contributor.committee | Agosto, José | |
dc.contributor.committee | Rodriguez-Martinez, José A | |
dc.contributor.campus | University of Puerto Rico, Río Piedras Campus | en_US |
dc.description.graduationSemester | Spring (2nd Semester) | en_US |
dc.description.graduationYear | 2022 | en_US |
thesis.degree.discipline | Biology | en_US |
thesis.degree.level | Ph.D. | en_US |