PMID- 25713333
OWN - NLM
STAT- MEDLINE
DCOM- 20160316
LR  - 20230718
IS  - 1538-8514 (Electronic)
IS  - 1535-7163 (Print)
IS  - 1535-7163 (Linking)
VI  - 14
IP  - 3
DP  - 2015 Mar
TI  - Multiple molecular subtypes of triple-negative breast cancer critically rely on 
      androgen receptor and respond to enzalutamide in vivo.
PG  - 769-78
LID - 10.1158/1535-7163.MCT-14-0926 [doi]
AB  - Triple-negative breast cancer (TNBC) has the lowest 5-year survival rate of 
      invasive breast carcinomas, and currently there are no approved targeted 
      therapies for this aggressive form of the disease. The androgen receptor (AR) is 
      expressed in up to one third of TNBC and we find that all AR(+) TNBC primary 
      tumors tested display nuclear localization of AR, indicative of transcriptionally 
      active receptors. While AR is most abundant in the "luminal AR (LAR)" molecular 
      subtype of TNBC, here, for the first time, we use both the new-generation 
      anti-androgen enzalutamide and AR knockdown to demonstrate that the other non-LAR 
      molecular subtypes of TNBC are critically dependent on AR protein. Indeed, AR 
      inhibition significantly reduces baseline proliferation, anchorage-independent 
      growth, migration, and invasion and increases apoptosis in four TNBC lines 
      (SUM159PT, HCC1806, BT549, and MDA-MB-231), representing three non-LAR TNBC 
      molecular subtypes (mesenchymal-like, mesenchymal stem-like, and basal-like 2). 
      In vivo, enzalutamide significantly decreases viability of SUM159PT and HCC1806 
      xenografts. Furthermore, mechanistic analysis reveals that AR activation 
      upregulates secretion of the EGFR ligand amphiregulin (AREG), an effect abrogated 
      by enzalutamide in vitro and in vivo. Exogenous AREG partially rescues the 
      effects of AR knockdown on proliferation, migration, and invasion, demonstrating 
      that upregulation of AREG is one mechanism by which AR influences tumorigenicity. 
      Together, our findings indicate that non-LAR subtypes of TNBC are AR dependent 
      and, moreover, that enzalutamide is a promising targeted therapy for multiple 
      molecular subtypes of AR(+) TNBC.
CI  - (c)2015 American Association for Cancer Research.
FAU - Barton, Valerie N
AU  - Barton VN
AD  - Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, 
      Colorado.
FAU - D'Amato, Nicholas C
AU  - D'Amato NC
AD  - Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, 
      Colorado.
FAU - Gordon, Michael A
AU  - Gordon MA
AD  - Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, 
      Colorado.
FAU - Lind, Hanne T
AU  - Lind HT
AD  - Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, 
      Colorado.
FAU - Spoelstra, Nicole S
AU  - Spoelstra NS
AD  - Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, 
      Colorado.
FAU - Babbs, Beatrice L
AU  - Babbs BL
AD  - Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, 
      Colorado.
FAU - Heinz, Richard E
AU  - Heinz RE
AD  - Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, 
      Colorado.
FAU - Elias, Anthony
AU  - Elias A
AD  - Department of Medicine, Division of Oncology, University of Colorado Anschutz 
      Medical Campus, Aurora, Colorado.
FAU - Jedlicka, Paul
AU  - Jedlicka P
AD  - Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, 
      Colorado.
FAU - Jacobsen, Britta M
AU  - Jacobsen BM
AD  - Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, 
      Colorado.
FAU - Richer, Jennifer K
AU  - Richer JK
AD  - Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, 
      Colorado. Jennifer.Richer@ucdenver.edu.
LA  - eng
GR  - R01 CA187733/CA/NCI NIH HHS/United States
GR  - F31 CA192807/CA/NCI NIH HHS/United States
GR  - P30CA046934/CA/NCI NIH HHS/United States
GR  - BC120183/BC/NCI NIH HHS/United States
GR  - P30 CA046934/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20150223
PL  - United States
TA  - Mol Cancer Ther
JT  - Molecular cancer therapeutics
JID - 101132535
RN  - 0 (AR protein, human)
RN  - 0 (Androgen Antagonists)
RN  - 0 (Benzamides)
RN  - 0 (Nitriles)
RN  - 0 (Receptors, Androgen)
RN  - 2010-15-3 (Phenylthiohydantoin)
RN  - 93T0T9GKNU (enzalutamide)
SB  - IM
MH  - Androgen Antagonists/pharmacology
MH  - Animals
MH  - Apoptosis/drug effects/genetics
MH  - Benzamides
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects/genetics
MH  - Female
MH  - Gene Expression Regulation, Neoplastic/drug effects/genetics
MH  - Humans
MH  - Mice
MH  - Mice, Nude
MH  - Nitriles
MH  - Phenylthiohydantoin/*analogs & derivatives/pharmacology
MH  - Receptors, Androgen/*genetics
MH  - Signal Transduction/drug effects/genetics
MH  - Triple Negative Breast Neoplasms/*drug therapy/*genetics
PMC - PMC4534304
MID - NIHMS700660
COIS- Disclosure of Potential Conflicts of Interest A. Elias has received other 
      commercial research support from Medivation and Astellas. No potential conflicts 
      of interest were disclosed by the other authors.
EDAT- 2015/02/26 06:00
MHDA- 2016/03/17 06:00
PMCR- 2015/08/12
CRDT- 2015/02/26 06:00
PHST- 2014/10/22 00:00 [received]
PHST- 2015/01/11 00:00 [accepted]
PHST- 2015/02/26 06:00 [entrez]
PHST- 2015/02/26 06:00 [pubmed]
PHST- 2016/03/17 06:00 [medline]
PHST- 2015/08/12 00:00 [pmc-release]
AID - 1535-7163.MCT-14-0926 [pii]
AID - 10.1158/1535-7163.MCT-14-0926 [doi]
PST - ppublish
SO  - Mol Cancer Ther. 2015 Mar;14(3):769-78. doi: 10.1158/1535-7163.MCT-14-0926. Epub 
      2015 Feb 23.