title: Progesterone stimulates proliferation and promotes cytoplasmic localization of the cell cycle inhibitor p27 in steroid receptor positive breast cancers.
abstract: Progestins are reported to increase the risk of more aggressive estrogen receptor positive, progesterone receptor positive (ER+ PR+) breast cancers in postmenopausal women. Using an in vivo rat model of ER+ PR + mammary cancer, we show that tumors arising in the presence of estrogen and progesterone exhibit increased proliferation and decreased nuclear expression of the cell cycle inhibitor p27 compared with tumors growing in the presence of estrogen alone. In human T47D breast cancer cells, progestin increased proliferation and decreased nuclear p27 expression. The decrease of nuclear p27 protein was dependent on activation of Src and PI3K by progesterone receptor isoforms PRA or PRB. Importantly, increased proliferation and decreased nuclear p27 expression were observed in invasive breast carcinoma compared with carcinoma in situ. These results suggest that progesterone specifically regulates intracellular localization of p27 protein and proliferation. Therefore, progesterone-activated pathways can provide useful therapeutic targets for treatment of more aggressive ER+ PR+ breast cancers.
authors.affiliation: Department of Physiology, College of Human Medicine, Michigan State University, East Lansing, MI, USA, kariagin@msu.edu.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Kariagina
authors.forename: Jianwei
authors.initials: J
authors.lastname: Xie
authors.forename: Ingeborg M
authors.initials: IM
authors.lastname: Langohr
authors.forename: Razvan C
authors.initials: RC
authors.lastname: Opreanu
authors.forename: Marc D
authors.initials: MD
authors.lastname: Basson
authors.forename: Sandra Z
authors.initials: SZ
authors.lastname: Haslam
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D058990:Molecular Targeted Therapy; D011374:Progesterone / Q000378:metabolism*; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D004967:Estrogens; D011374:Progesterone