Authors: Izzo, Franco; Mercogliano, María Florencia; Venturutti, Leandro; Tkach, Mercedes; Inurrigarro, Gloria; Schillaci, Roxana; Cerchietti, Leandro; Elizalde, Patricia Virginia; Proietti Anastasi, Cecilia Jazmín
Publication Date: 2014.
Language: English.
Abstract:
The transcription factor GATA3 is involved in mammary gland development and is crucial for the maintenance of the differentiated status of luminal epithelial cells. The role of GATA3 in breast cancer as a tumor suppressor has been established, although insights into the mechanism of GATA3 expression loss are still required.
Author affiliation: Izzo, Franco. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Author affiliation: Mercogliano, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Author affiliation: Venturutti, Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Author affiliation: Tkach, Mercedes. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Author affiliation: Inurrigarro, Gloria. Sanatorio Mater Dei Hermanas de María de Schoenstatt; Argentina
Author affiliation: Schillaci, Roxana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Author affiliation: Cerchietti, Leandro. Weill Cornell Medical College; Estados Unidos
Author affiliation: Elizalde, Patricia Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Author affiliation: Proietti Anastasi, Cecilia Jazmín. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas
Authors: Wiebe, John P.; Rivas, Martin Alfredo; Mercogliano, María Florencia; Elizalde, Patricia Virginia; Schillaci, Roxana
Publication Date: 2015.
Language: English.
Abstract:
Progesterone has long been linked to breast cancer but its actual role as a cancer promoter has remained in dispute. Previous in vitro studies have shown that progesterone is converted to 5a-dihydroprogesterone (5aP) in breast tissue and human breast cell lines by the action of 5 a-reductase, and that 5aP acts as a cancer-promoter hormone. Also studies with human breast cell lines in which the conversion of progesterone to 5aP is blocked by a 5a-reductase inhibitor, have shown that the in vitro stimulation in cell proliferation with progesterone treatments are not due to progesterone itself but to the metabolite 5aP. No similar in vivo study has been previously reported. The objective of the current studies was to determine in an in vivo mouse model if the presumptive progesterone-induced mammary tumorigenesis is due to the progesterone metabolite, 5aP. BALB/c mice were challenged with C4HD murine mammary cells, which have been shown to form tumors when treated with progesterone or the progestin, medroxyprogesterone acetate. Cells and mice were treated with various doses and combinations of progesterone, 5aP and/or the 5 a-reductase inhibitor, finasteride, and the effects on cell proliferation and induction and growth of tumors were monitored. Hormone levels in serum and tumors were measured by specific RIA and ELISA tests. Proliferation of C4HD cells and induction and growth of tumors was stimulated by treatment with either progesterone or 5aP. The progesterone-induced stimulation was blocked by finasteride and reinstated by concomitant treatment with 5aP. The 5aP-induced tumors expressed high levels of ER, PR and ErbB-2. Hormone measurements showed significantly higher levels of 5aP in serum from mice with tumors than from mice without tumors, regardless of treatments, and 5aP levels were significantly higher (about 4-fold) in tumors than in respective sera, while progesterone levels did not differ between the compartments. The results indicate that the stimulation of C4HD tumor growth in BALB/c mice treated with progesterone is due to the progesterone metabolite 5aP formed at elevated levels in mammary cells as a result of the 5a-reductase action on progesterone. The results provide the first in vivo demonstration that stimulation of breast cell tumorigenesis and tumor growth accompanying progesterone treatment is due to the progesterone metabolite 5aP, and that breast tumorigenesis can be blocked with the 5a-reductase inhibitor, finasteride.
Author affiliation: Wiebe, John P.. University of Wenstern Ontario. Department of Biology; Canadá
Author affiliation: Rivas, Martin Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Author affiliation: Mercogliano, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Author affiliation: Elizalde, Patricia Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Author affiliation: Schillaci, Roxana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas