Reversal of antiprogestin resistance and progesterone receptor isoform ratio in acquired resistant mammary carcinomas.
To explore mechanisms related to hormone resistance, three resistant variants of the MPA mouse breast cancer tumor model with low levels of progesterone receptor (PR) isoform A (PR-A)/high PR-B expression were developed by prolonged selective pressure with antiprogestins. The resistant phenotype of one tumor line was reversed spontaneously after several consecutive passages in syngeneic BALB/c mice or by 17-beta-estradiol or tamoxifen treatment, and this reversion was significantly associated with an increase in PR-A expression. The responsive parental tumors disclosed low activation of ERK and high activation of AKT; resistant tumors on the other hand, showed the opposite, and this was associated with a higher metastatic potential, that did not revert. This study shows for the first time in vivo a relationship between PR isoform expression and antiprogestin responsiveness, demonstrating that, whereas acquired resistance may be reversed, changes in kinase activation and metastatic potential are unidirectional associated with tumor progression.
Wargon
Victoria
V
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine-National Research Council of Argentina (CONICET), Obligado 2490, 1428 Buenos Aires, Argentina.
Helguero
Luisa A
LA
Bolado
Julieta
J
Rojas
Paola
P
Novaro
Virginia
V
Molinolo
Alfredo
A
Lanari
Claudia
C
D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D005260:Female; D005455:Fluorescent Antibody Technique; D006727:Hormone Antagonists / Q000494:pharmacology*; D008207:Lymphatic Metastasis; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D015735:Mifepristone / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020033:Protein Isoforms; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism*; D015996:Survival Rate
D006727:Hormone Antagonists; D020033:Protein Isoforms; D011980:Receptors, Progesterone; C101118:progesterone receptor A; C097314:progesterone receptor B; D015735:Mifepristone; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3