INVESTIGADORES
ROSEMBLIT Cinthia
congresos y reuniones científicas
Título:
AP-1 transcription factor is involved in breast cancer cell proliferation mediated by progestins
Autor/es:
DIAZ FLAQUE MC; BEGUELIN W; ROSEMBLIT C; PROIETTI CJ; RIVAS MA ; TKACH M; CHARREAU EH; SCHILLACI R; ELIZALDE PV
Lugar:
Washingtong, DC
Reunión:
Congreso; American Association for Cancer Research 101st Annual meeting; 2010
Institución organizadora:
American Association for Cancer Research (AACR)
Resumen:
Accumulating
evidence has shown the involvement of the progesterone receptor (PR) in
breast cancer development. We and others have also shown that progestin
are able to induce cyclin D1 expression, a key regulatory molecule that
does not contain a progesterone response element (PRE) in the promoter
region. In the present study, we propose a novel mechanism in which
progestin controls breast cancer growth through the integration of rapid
PR signaling and a transcriptional mechanism (tethering), that involves
progesterone-bound PR interaction with AP-1 transcription factor
(composed of Jun and Fos family members), at specific AP-1 binding sites
(TRE) in the cyclin D1 promoter. MPA treatment of breast cancer cells
induced an increase in the levels of cyclin D1 protein. We have also
shown that MPA treatment of breast cancer cells induced an increase in
the levels of c-jun and c-fos phosphorylation. To study the effect of
MPA on AP-1-mediated transcriptional activity, cells were transiently
transfected with a luciferase reporter plasmid containing three copies
of TRE. We found that MPA enhanced AP-1 transcriptional activity and
this effect was abolished by the antiprogestin RU486. We assessed the
specific association of AP-1 and PR to the TRE region of the cyclin D1
gene in the context of living cells, by performing Chromatin
Immunoprecipitation Assays. We found that MPA treatment induced c-jun,
c-fos and PR recruitment to the cyclin D1 promoter. These data identify,
for the first time, the interaction between AP-1 and PR regulating
cyclin D1 transcription by tethering to DNA-bound at TRE site.
Furthermore, we found that the inhibition of c-fos and c-jun activation
by the use of dominant negative forms of these proteins (A-Fos and
TAM-67 respectively) completely blocked progestin-induced cyclin D1
expression and in vitro breast cancer cell growth. Finally, we addressed
the effect of targeting AP-1 in in vivo MPA-dependent growth of C4HD
progestin-dependent murine mammary tumor. Transfection of C4HD cells
with TAM-67 or A-Fos DN expression vectors significantly inhibited these
cells? ability to form tumors in syngeneic mice. Histological
examination determined a striking decrease in histological grade in both
groups in comparison to control group.