title: Glucocorticoid receptor activity discriminates between progesterone and medroxyprogesterone acetate effects in breast cells.
abstract: The purpose of this article is to determine the tumorigenic potential of estradiol treatment (E2) when combined with either progesterone (P4) or medroxyprogesterone acetate (MPA) in normal luminal human breast cells (HBE) and in human breast cancer cells (T47-D, MCF-7). Proliferation profiles were evaluated, along with the gene transactivation activity between the progesterone and glucocorticoid receptors (PR, GR) in HBE, T47-D, and MCF-7 cells treated by E2 + P4 or E2 + MPA. High throughput transcriptome analysis was performed on RNA from HBE cells treated by E2, E2 + MPA and E2 + P4. GR content was analyzed in normal breast cells as well. In HBE cells, E2 + P4 treatment was antiproliferative and promoted cellular differentiation. In contrast, E2 + MPA displayed mitogenic, antiapoptotic effects in HBE cells and did not influence cellular differentiation. The effect of P4 and MPA on cell proliferation was, however, variable in breast cancer cells. In cells containing GR or/and PR, MPA decreased proliferation whereas P4 antiproliferative effect needed the presence of PR. In HBE cells, the regulation of genes by E2 + P4, and E2 + MPA was significantly different, particularly in cell proliferation and cell death gene families. Further analysis revealed a modulation of the glucocorticoid receptor gene expression pathway by E2 + MPA. Predominant MPA glucocorticoid activity in normal and breast cancer cells was demonstrated using a glucocorticoid antagonist and the down-regulation of the GR by RNA interference. In normal luminal breast cells and in breast cancer cells, P4 and MPA combined with E2 treatment have opposing mitogenic effects due to GR. The consequences of MPA glucocorticoid potencies as well as the importance of GR in breast tissue merit a reappraisal.
authors.affiliation: INSERM-UPMC, UMRS 938, Hôpital Saint-Antoine, Paris, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Courtin
authors.forename: Laudine
authors.initials: L
authors.lastname: Communal
authors.forename: Myriam
authors.initials: M
authors.lastname: Vilasco
authors.forename: Daniela
authors.initials: D
authors.lastname: Cimino
authors.forename: Najat
authors.initials: N
authors.lastname: Mourra
authors.forename: Michele
authors.initials: M
authors.lastname: de Bortoli
authors.forename: Daniela
authors.initials: D
authors.lastname: Taverna
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Faussat
authors.forename: Marc
authors.initials: M
authors.lastname: Chaouat
authors.forename: Patricia
authors.initials: P
authors.lastname: Forgez
authors.forename: Anne
authors.initials: A
authors.lastname: Gompel
mesh_terms: D000293:Adolescent; D000328:Adult; D001940:Breast; D001943:Breast Neoplasms; D002352:Carrier Proteins / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D059014:High-Throughput Nucleotide Sequencing; D020249:Hormone Replacement Therapy / Q000379:methods; D006801:Humans; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology*; D009649:Norpregnadienes / Q000494:pharmacology; D011374:Progesterone / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism*; D013256:Steroids; D059467:Transcriptome; D055815:Young Adult
chemical_list: D002352:Carrier Proteins; D009649:Norpregnadienes; C110451:ORG-34116; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D011965:Receptors, Glucocorticoid; D011980:Receptors, Progesterone; D013256:Steroids; D011374:Progesterone; D004958:Estradiol; C094854:ulipristal; D017258:Medroxyprogesterone Acetate