Regresión de cáncer de mama después del tratamiento hormonal en un modelo murino / Mammary cancer regression after hormonal treatment in a murine model

Carcinomas mamarios murinos, originalmente inducidos por acetato de medroxiprogesterona, con crecimiento autónomo y receptores de estrógenos y progesterona regresionan con estradiol (E2) o con antiprogestágenos. Con el objeto de analizar los mecanismos de la regresión tumoral, estudiamos las características morfológicas y la participación de los reguladores del ciclo celular tales como p21, p27, p53 y MDM2 mediante inmunohistoquímica utilizando dos tumores sensibles al E2 o a los antiprogestágenos y uno sensible al E2 y antiprogestágenos resistente. La regresión se asocia a disminución del parénquima tumoral con aumento del estroma, a un efecto antiproliferativo y proapoptótico y a la inducción de proteínas inhibitorias del ciclo celular tales como p21 y p27. Sin embargo el patrón de expresión de los reguladores del ciclo celular varió. En los tumores sensibles a ambos tratamientos aumentó p21 y p27, los valores basales de p53 fueron altos y los de MDM2 bajos. En el tumor sensible sólo a E2 aumentó únicamente p27 y p21 permaneció en valores bajos acompañados por altos niveles basales de p53 y MDM2. Estos hallazgos sugieren que p21 podría ser esencial para la acción de los antiprogestágenos y que alteraciones en la vía p21/p53 podrían participar en la resistencia al tratamiento hormonal.

Regresión de cáncer de mama después del tratamiento hormonal en un modelo murino / Mammary cancer regression after hormonal treatment in a murine model

Carcinomas mamarios murinos, originalmente inducidos por acetato de medroxiprogesterona, con crecimiento autónomo y receptores de estrógenos y progesterona regresionan con estradiol (E2) o con antiprogestágenos. Con el objeto de analizar los mecanismos de la regresión tumoral, estudiamos las características morfológicas y la participación de los reguladores del ciclo celular tales como p21, p27, p53 y MDM2 mediante inmunohistoquímica utilizando dos tumores sensibles al E2 o a los antiprogestágenos y uno sensible al E2 y antiprogestágenos resistente. La regresión se asocia a disminución del parénquima tumoral con aumento del estroma, a un efecto antiproliferativo y proapoptótico y a la inducción de proteínas inhibitorias del ciclo celular tales como p21 y p27. Sin embargo el patrón de expresión de los reguladores del ciclo celular varió. En los tumores sensibles a ambos tratamientos aumentó p21 y p27, los valores basales de p53 fueron altos y los de MDM2 bajos. En el tumor sensible sólo a E2 aumentó únicamente p27 y p21 permaneció en valores bajos acompañados por altos niveles basales de p53 y MDM2. Estos hallazgos sugieren que p21 podría ser esencial para la acción de los antiprogestágenos y que alteraciones en la vía p21/p53 podrían participar en la resistencia al tratamiento hormonal. (AU)

Hormone dependence of a mouse mammary tumor line induced in vivo by medroxyprogesterone acetate.

The administration of MPA to virgin female BALB/c mice led to the development of mammary adenocarcinomas, which in further in vivo transplants gave rise to both MPA-dependent and MPA-independent lines. In this paper we chose one of the MPA-dependent lines with high contents of estrogen (ER) and progesterone (PR) receptors, and were able to demonstrate that a) the growth of these tumors could be manipulated by the administration or the withdrawal of the hormonal supply; b) PR were down-regulated in MPA-treated mice; c) progesterone had the same stimulatory effect as MPA on tumor growth; d) tumors did not grow in estrogen-treated mice; e) tumor growth was much lower in males than in females; f) the presence of the ovaries had a positive influence on tumor growth, even in the presence of MPA; g) the withdrawal of progestin pellets in ovariectomized mice usually led to complete remissions followed by regrowth of the tumors after several weeks; and h) the regrowing tumors maintained their steroid receptor pattern and (in 3 out of 4 cases) their hormone-dependent behavior in further passages.

Transforming growth factor-beta activities in 'in vivo' lines of hormone-dependent and independent mammary adenocarcinomas induced by medroxyprogesterone acetate in BALB/c mice.

We have determined the presence of transforming growth factor-beta (TGF-beta)-like polypeptides in mammary adenocarcinomas induced by medroxyprogesterone acetate (MPA) in BALB/c mice. In hormone-dependent tumors (HD) from nontreated and MPA-treated mice a high molecular weight (43 kDa) transforming activity was purified by Bio-Gel P-60 chromatography. This TGF was able to confer the neoplastic phenotype on NRK-49F cells without the addition of epidermal growth factor (EGF), though its activity was potentiated by EGF. It did not compete for binding to the EGF receptor, had no mitogenic activity on monolayer cultures of NRK fibroblasts, and was a potent inhibitor of DNA synthesis induced in these cells by EGF and insulin. In HD and hormone-independent tumors (HI) another TGF with a Mr of 13 kDa was isolated. This transforming activity showed the same biological properties as 43 kDa TGF, with the exception that in the absence of EGF it did not stimulate soft agar growth of NRK-49F cells. The synthesis of both factors in 'in vivo' HD tumors seems to be under MPA control, since it is much lower in HD tumors from MPA-treated mice. Further purification of the 13 and 43 kDa TGFs by hydrophobic interaction HPLC demonstrated that each one eluted in a different position, and that their elution profile differed from the TGF-beta from human platelets. The biological activity of the 13 and 43 kDa TGFs was not neutralized by a specific anti-TGF-beta antibody.

Mouse mammary tumors induced by medroxyprogesterone acetate: immunohistochemistry and hormonal receptors.

Mammary adenocarcinomas induced by medroxyprogesterone acetate (MPA) in female BALB/c mice were investigated as to their morphology and immunohistochemistry and their content of steroid, prolactin (PRL), and epidermal growth factor (EGF) receptors. Histologically, these tumors were mainly of ductal origin, since hyperplastic alveolar nodules were observed only in 3 cases. No viral particles were encountered in electron microscopic studies. Estrogen and/or progesterone, PRL, and EGF receptors were detected in MPA-induced tumors, as well as in the occasional spontaneous mammary tumors of multiparous females. EGF was detected, by a radioimmunoassay, in the cystic fluid of 12 mammary adenocarcinomas. MPA treatment was found to induce uterine secretory changes, glandular cystic hyperplasia, and eventually deciduomas that stained strongly for desmin and to a lesser degree for vimentin, suggesting a muscular differentiation. Consequently, MPA-induced adenocarcinomas can be considered as ductal tumors that possess estrogen and/or progesterone, PRL, and EGF receptors. Whether MPA induces tumor growth directly via progesterone receptors remains to be investigated.