PMID- 23029355
OWN - NLM
STAT- MEDLINE
DCOM- 20130305
LR  - 20220409
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 7
IP  - 9
DP  - 2012
TI  - Differential regulation of breast cancer-associated genes by progesterone 
      receptor isoforms PRA and PRB in a new bi-inducible breast cancer cell line.
PG  - e45993
LID - 10.1371/journal.pone.0045993 [doi]
LID - e45993
AB  - Progesterone receptor isoforms (PRA and PRB) are expressed at equal levels in 
      normal mammary cells. However, alteration in PRA/PRB expression is often observed 
      in aggressive breast cancer suggesting differential contribution of PR isoforms 
      in carcinogenesis. The mechanisms underlying such processes remain to be 
      established mainly due to paucity of appropriate cellular models. To investigate 
      the role of PR isoforms and the impact of imbalanced PRA/PRB ratio in 
      transcriptional regulation, we have generated an original human breast cancer 
      cell line conditionally expressing PRA and/or PRB in dose-dependence of 
      non-steroid inducers. We first focused on PR-dependent transcriptional regulation 
      of the paracrine growth factor gene amphiregulin (AREG) playing important role in 
      cancer. Interestingly, unliganded PRA increases AREG expression, independently of 
      estrogen receptor, yet inhibitable by antiprogestins. We show that functional 
      outcome of epidermal growth factor (EGF) on such regulation is highly dependent 
      on PRA/PRB ratio. Using this valuable model, genome-wide transcriptomic studies 
      allowed us to determine the differential effects of PRA and PRB as a function of 
      hormonal status. We identified a large number of novel PR-regulated genes notably 
      implicated in breast cancer and metastasis and demonstrated that imbalanced 
      PRA/PRB ratio strongly impact their expression predicting poor outcome in breast 
      cancer. In sum, our unique cell-based system strongly suggests that PRA/PRB ratio 
      is a critical determinant of PR target gene selectivity and responses to 
      hormonal/growth factor stimuli. These findings provide molecular support for the 
      aggressive phenotype of breast cancers with impaired expression of PRA or PRB.
FAU - Khan, Junaid A
AU  - Khan JA
AD  - Institut National de la Sante et de la Recherche Medicale Unite, Steroid 
      Receptors: Endocrine and Metabolic Pathophysiology, Le Kremlin-Bicetre, France.
FAU - Bellance, Catherine
AU  - Bellance C
FAU - Guiochon-Mantel, Anne
AU  - Guiochon-Mantel A
FAU - Lombes, Marc
AU  - Lombes M
FAU - Loosfelt, Hugues
AU  - Loosfelt H
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120924
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (AREG protein, human)
RN  - 0 (Amphiregulin)
RN  - 0 (EGF Family of Proteins)
RN  - 0 (Glycoproteins)
RN  - 0 (HBEGF protein, human)
RN  - 0 (Heparin-binding EGF-like Growth Factor)
RN  - 0 (Hormone Antagonists)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (Protein Isoforms)
RN  - 0 (Receptors, Progesterone)
RN  - 0 (progesterone receptor A)
RN  - 0 (progesterone receptor B)
RN  - 320T6RNW1F (Mifepristone)
SB  - IM
MH  - Amphiregulin
MH  - Breast/cytology/metabolism/pathology
MH  - Breast Neoplasms/*genetics/metabolism/pathology
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - EGF Family of Proteins
MH  - Female
MH  - *Gene Expression Regulation, Neoplastic
MH  - Glycoproteins/genetics
MH  - Heparin-binding EGF-like Growth Factor
MH  - Hormone Antagonists/pharmacology
MH  - Humans
MH  - Intercellular Signaling Peptides and Proteins/genetics/metabolism
MH  - Mifepristone/pharmacology
MH  - Protein Isoforms/genetics/metabolism
MH  - Receptors, Progesterone/*genetics/metabolism
MH  - Transcriptional Activation
PMC - PMC3454371
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2012/10/03 06:00
MHDA- 2013/03/06 06:00
PMCR- 2012/09/24
CRDT- 2012/10/03 06:00
PHST- 2012/04/27 00:00 [received]
PHST- 2012/08/23 00:00 [accepted]
PHST- 2012/10/03 06:00 [entrez]
PHST- 2012/10/03 06:00 [pubmed]
PHST- 2013/03/06 06:00 [medline]
PHST- 2012/09/24 00:00 [pmc-release]
AID - PONE-D-12-12535 [pii]
AID - 10.1371/journal.pone.0045993 [doi]
PST - ppublish
SO  - PLoS One. 2012;7(9):e45993. doi: 10.1371/journal.pone.0045993. Epub 2012 Sep 24.