TY - JOUR
T1 - Progesterone receptor expression in medroxyprogesterone acetate-induced murine mammary carcinomas and response to endocrine treatment
AU - Helguero, Luisa A.
AU - Viegas, Marcelo
AU - Asaithamby, Aroumougame
AU - Shyamala, Gopalan
AU - Lanari, Claudia
AU - Molinolo, Alfredo A.
N1 - Funding Information:
We are grateful to Dr M. Schneider from Schering Germany for kindly providing ZK 98299, Roussel Uclaf for providing RU 38486, and Gador Laboratories, Buenos Aires for providing the MPA. We are also grateful to Dr M. Goin for helpful suggestions with the western blots, to Miss G. Aznarez and J. Bolado for excellent technical assistance in animal care. This work was supported by grants from SECyT BID 1201/OC-AR PICT99 05-06389, Fundación Sales, and NIH, CA66541 to GS.
PY - 2003/6
Y1 - 2003/6
N2 - Using medroxyprogesterone acetate (MPA) as a carcinogen, we were able to induce in BALB/c female mice, several progestin-dependent mammary ductal carcinomas that regress completely with estrogen or antiprogestins and are maintained by serial transplantations in syngeneic mice. Progestin-independent variants were subsequently generated or appeared spontaneously. Based on their response to estrogen or antiprogestins, we subdivided them into responsive progestin-independent (R-PI) variants which regress completely and unresponsive progestin-independent (UR-PI) carcinomas which are resistant to both families of compounds. In this study we have investigated progesterone receptor (PR) expression in six responsive progestin-dependent, six R-PI, and three UR-PI tumors. Progestin-dependent and R-PI tumors disclosed a higher expression of the PRA isoform as compared with PRB, as well as an additional band of 78 kDa that was not detected in uterine tissue; all were down-regulated by progestins. UR-PI tumors expressed lower levels of all bands in western blots, but were highly reactive by immuno-histochemistry. PR RNA expression was detected in both, UR-PI and R-PI tumors. PR binding was comparable in progestin-dependent and R-PI tumors. In the three UR-PI tumors, only 29/61 (48%) of the samples evaluated showed low binding levels, the rest were negative. This report is the first to describe in an experimental model of breast cancer the expression of PR isoforms and their distribution. Our results suggest the expression of functionally altered isoforms in a subgroup of mammary carcinomas, which may explain their lack of hormone response.
AB - Using medroxyprogesterone acetate (MPA) as a carcinogen, we were able to induce in BALB/c female mice, several progestin-dependent mammary ductal carcinomas that regress completely with estrogen or antiprogestins and are maintained by serial transplantations in syngeneic mice. Progestin-independent variants were subsequently generated or appeared spontaneously. Based on their response to estrogen or antiprogestins, we subdivided them into responsive progestin-independent (R-PI) variants which regress completely and unresponsive progestin-independent (UR-PI) carcinomas which are resistant to both families of compounds. In this study we have investigated progesterone receptor (PR) expression in six responsive progestin-dependent, six R-PI, and three UR-PI tumors. Progestin-dependent and R-PI tumors disclosed a higher expression of the PRA isoform as compared with PRB, as well as an additional band of 78 kDa that was not detected in uterine tissue; all were down-regulated by progestins. UR-PI tumors expressed lower levels of all bands in western blots, but were highly reactive by immuno-histochemistry. PR RNA expression was detected in both, UR-PI and R-PI tumors. PR binding was comparable in progestin-dependent and R-PI tumors. In the three UR-PI tumors, only 29/61 (48%) of the samples evaluated showed low binding levels, the rest were negative. This report is the first to describe in an experimental model of breast cancer the expression of PR isoforms and their distribution. Our results suggest the expression of functionally altered isoforms in a subgroup of mammary carcinomas, which may explain their lack of hormone response.
KW - Hormone dependence
KW - Hormone response
KW - Immunohistochemistry
KW - Mammary carcinomas
KW - Mice
KW - Progesterone receptor isoforms
KW - Western blot
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U2 - 10.1023/A:1024029826248
DO - 10.1023/A:1024029826248
M3 - Article
C2 - 12846422
AN - SCOPUS:0037899633
SN - 0167-6806
VL - 79
SP - 379
EP - 390
JO - Breast Cancer Research and Treatment
JF - Breast Cancer Research and Treatment
IS - 3
ER -