| Autor: |
Sahores A; Instituto de Biología y Medicina Experimental (IBYME), CONICET, Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina., Figueroa V; Instituto de Biología y Medicina Experimental (IBYME), CONICET, Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina., May M; Instituto de Biología y Medicina Experimental (IBYME), CONICET, Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina., Liguori M; Hospital de Agudos Magdalena V de Martínez, General Pacheco, Argentina., Rubstein A; Merck Argentina, Buenos Aires, Argentina., Fuentes C; Instituto de Biología y Medicina Experimental (IBYME), CONICET, Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina., Jacobsen BM; Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA., Elía A; Instituto de Biología y Medicina Experimental (IBYME), CONICET, Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina., Rojas P; Instituto de Biología y Medicina Experimental (IBYME), CONICET, Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina., Sequeira GR; Instituto de Biología y Medicina Experimental (IBYME), CONICET, Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina., Álvarez MM; Instituto de Biología y Medicina Experimental (IBYME), CONICET, Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina., González P; Hospital de Agudos Magdalena V de Martínez, General Pacheco, Argentina., Gass H; Hospital de Agudos Magdalena V de Martínez, General Pacheco, Argentina., Hewitt S; NIDCR-NIH, Bethesda, MD, USA., Molinolo A; Moores Cancer Center, University of California San Diego, La Jolla, CA, USA., Lanari C; Instituto de Biología y Medicina Experimental (IBYME), CONICET, Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina., Lamb CA; Instituto de Biología y Medicina Experimental (IBYME), CONICET, Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina. carolinealamb@gmail.com. |
| Abstrakt: |
Endocrine resistance may develop as a consequence of enhanced growth factor signaling. Fibroblast growth factor 2 (FGF2) consists of a low and several high molecular weight forms (HMW-FGF2). We previously demonstrated that antiprogestin-resistant mammary carcinomas display lower levels of progesterone receptor A isoforms (PRA) than B isoforms (PRB). Our aim was to evaluate the role of FGF2 isoforms in breast cancer progression. We evaluated FGF2 expression, cell proliferation, and pathway activation in models with different PRA/PRB ratios. We performed lentiviral infections of different FGF2 isoforms using the human hormone-responsive T47D-YA cells, engineered to only express PRA, and evaluated tumor growth, metastatic dissemination, and endocrine responsiveness. We assessed FGF2 expression and localization in 81 human breast cancer samples. Antiprogestin-resistant experimental mammary carcinomas with low PRA/PRB ratios and T47D-YB cells, which only express PRB, displayed higher levels of HMW-FGF2 than responsive variants. HMW-FGF2 overexpression in T47D-YA cells induced increased tumor growth, lung metastasis, and antiprogestin resistance compared to control tumors. In human breast carcinomas categorized by their PRA/PRB ratio, we found nuclear FGF2 expression in 55.6% of tumor cells. No differences were found between nuclear FGF2 expression and Ki67 proliferation index, tumor stage, or tumor grade. In low-grade tumor samples, moderate to high nuclear FGF2 levels were associated to carcinomas with low PRA/PRB ratio. In conclusion, we show that HMW-FGF2 isoforms are PRB targets which confer endocrine resistance and are localized in the nuclei of breast cancer samples. Hence, targeting intracellular FGF2 may contribute to overcome tumor progression. |
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