title: Progestin effects on breast cancer cell proliferation, proteases activation, and in vivo development of metastatic phenotype all depend on progesterone receptor capacity to activate cytoplasmic signaling pathways.
abstract: Accumulating evidence indicates that progestins are involved in controlling mammary gland tumorigenesis. Here, we assessed the molecular mechanisms of progestin action in breast cancer models with different phenotypes. We examined C4HD cells, an estrogen (ER) and progesterone (PR) receptor-positive murine breast cancer model in which progestins exert sustained proliferative response, the LM3 murine metastatic mammary tumor cell line, which lacks PR and ER expression, and human PR null T47D-Y breast cancer cells. In addition to acting as a transcription factor, PR can also function as an activator of signaling pathways. To explore which of these two functions were involved in progestin responses, reconstitution experiments in the PR-negative models were performed with wild-type PR-B, with a DNA binding mutant C587A-PR, and with mutant PR-BmPro, which lacks the ability to activate cytoplasm signaling pathways. We found that in a cell context either ER-positive or -negative, progestins induced cell growth and modulation of matrix metalloproteinases-9 (MMP-9) and -2 (MMP-2), and urokinase-type plasminogen activator (uPA) activities, via MAPK and phosphatidylinositol 3-kinase/Akt pathways, in cells expressing wild-type PR-B or DNA binding mutant C587A-PR. In contrast, in cells expressing mutant PR-BmPro, progestins did not induce growth. We also found that unliganded PR expression conferred breast cancer cells an in vitro less proliferative phenotype, as compared with cells lacking PR expression. Modulation of this behavior occurred when PR was functioning either as transcription factor or as signaling activator. Finally, we for the first time demonstrated that progestins favor development of breast tumor metastasis via PR function as activator of signaling pathways. Our present findings provide mechanistic support to the design of a novel therapeutic intervention in PR-positive breast tumors involving blockage of PR capacity to activate cytoplasmic signaling.
authors: Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires C1428ADN, Argentina.
authors: Romina P
authors: RP
authors: Carnevale
authors: Cecilia J
authors: CJ
authors: Proietti
authors: Mariana
authors: M
authors: Salatino
authors: Alejandro
authors: A
authors: Urtreger
authors: Guillermo
authors: G
authors: Peluffo
authors: Dean P
authors: DP
authors: Edwards
authors: Viroj
authors: V
authors: Boonyaratanakornkit
authors: Eduardo H
authors: EH
authors: Charreau
authors: Elisa
authors: E
authors: Bal de Kier Joffé
authors: Roxana
authors: R
authors: Schillaci
authors: Patricia V
authors: PV
authors: Elizalde
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003593:Cytoplasm / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009362:Neoplasm Metastasis; D010447:Peptide Hydrolases / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011372:Progestins / Q000494:pharmacology*; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
chemical_list: D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D020929:Mitogen-Activated Protein Kinase Kinases; D010447:Peptide Hydrolases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011372:Progestins; D011980:Receptors, Progesterone; D014568:Urokinase-Type Plasminogen Activator