title: Quantitative analysis of gene regulation by seven clinically relevant progestins suggests a highly similar mechanism of action through progesterone receptors in T47D breast cancer cells.
abstract: Progesterone (P4) is an essential reproductive steroid hormone required for many aspects of female reproductive physiology. Progestins are compounds that demonstrate progesterone-like activity and are used in oral contraception, hormone therapy, and treatment of some reproductive disorders, but differ widely in their chemical structures, potency, and pharmacokinetics. While numerous studies have assessed progestins on specific endpoints, little is known about the activation of global gene expression by progestins. We used Affymetrix GeneChip U133A expression arrays to examine the action of P4 and six clinically relevant synthetic progestins (3-ketodesogestrel, drospirenone, levonorgestrel, medroxyprogesterone acetate, norethindrone acetate, and trimegestone) on the progesterone receptor (PR)-positive T47Dco and the PR-negative T47D-Y breast cancer cell lines. Excluding drospirenone, one or more of the progestins-regulated 329 genes, with 30 genes regulated by at least 2.0-fold by all progestins in the T47Dco cells. The synthetic progestins show a high degree of similarity in their transcriptional responses, and each progestin regulates between 77 and 91% of the genes regulated by P4. Independent quantitative RT-PCR analysis confirmed a similar regulation for S100P, PPL, IL20RA, NET1, ATP1A1, HIG2, and CXCL12 (SDF-1) by all seven progestins. Attempts to find differentially regulated genes by any progestin compared to all other treatments failed, suggesting any differences are quantitative, not qualitative. This analysis demonstrates a high degree of similarity among these progestins on PR-regulated gene expression in T47D cells, suggesting a similar and fairly specific mode of action.
authors.affiliation: Women's Health Research Institute, Wyeth Research, Collegeville, PA 19426, USA. jeffrey.d.bray@gsk.com
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Bray
authors.forename: Scott
authors.initials: S
authors.lastname: Jelinsky
authors.forename: Radhika
authors.initials: R
authors.lastname: Ghatge
authors.forename: Jenifer A
authors.initials: JA
authors.lastname: Bray
authors.forename: Christopher
authors.initials: C
authors.lastname: Tunkey
authors.forename: Kathryn
authors.initials: K
authors.lastname: Saraf
authors.forename: Britta M
authors.initials: BM
authors.lastname: Jacobsen
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Richer
authors.forename: Eugene L
authors.initials: EL
authors.lastname: Brown
authors.forename: Richard C
authors.initials: RC
authors.lastname: Winneker
authors.forename: Kathryn B
authors.initials: KB
authors.lastname: Horwitz
authors.forename: C Richard
authors.initials: CR
authors.lastname: Lyttle
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000736:Androstenes / Q000737:chemistry; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D017135:Desogestrel / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016912:Levonorgestrel / Q000737:chemistry; D008024:Ligands; D017258:Medroxyprogesterone Acetate / Q000737:chemistry; D020411:Oligonucleotide Array Sequence Analysis; D011374:Progesterone / Q000737:chemistry / Q000378:metabolism*; D011372:Progestins / Q000737:chemistry; D011397:Promegestone / Q000031:analogs & derivatives / Q000737:chemistry; D012313:RNA / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic
chemical_list: D000736:Androstenes; D008024:Ligands; D011372:Progestins; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C044815:etonogestrel; C050319:trimegestone; D011374:Progesterone; D016912:Levonorgestrel; D012313:RNA; D017135:Desogestrel; D011397:Promegestone; D017258:Medroxyprogesterone Acetate; D000469:Alkaline Phosphatase; C035144:drospirenone