title: Reversal of antiprogestin resistance and progesterone receptor isoform ratio in acquired resistant mammary carcinomas.
abstract: 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.
authors.affiliation: Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine-National Research Council of Argentina (CONICET), Obligado 2490, 1428 Buenos Aires, Argentina.
authors.forename: Victoria
authors.initials: V
authors.lastname: Wargon
authors.forename: Luisa A
authors.initials: LA
authors.lastname: Helguero
authors.forename: Julieta
authors.initials: J
authors.lastname: Bolado
authors.forename: Paola
authors.initials: P
authors.lastname: Rojas
authors.forename: Virginia
authors.initials: V
authors.lastname: Novaro
authors.forename: Alfredo
authors.initials: A
authors.lastname: Molinolo
authors.forename: Claudia
authors.initials: C
authors.lastname: Lanari
mesh_terms: 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
chemical_list: 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