Molecular and structural basis of androgen receptor responses to dihydrotestosterone, medroxyprogesterone acetate and Δ(4)-tibolone.
Medroxyprogesterone acetate (MPA) has widely been used in hormone replacement therapy (HRT), and is associated with an increased risk of breast cancer, possibly due to disruption of androgen receptor (AR) signaling. In contrast, the synthetic HRT Tibolone does not increase breast density, and is rapidly metabolized to estrogenic 3α-OH-tibolone and 3β-OH-tibolone, and a delta-4 isomer (Δ(4)-TIB) that has both androgenic and progestagenic properties. Here, we show that 5α-dihydrotestosterone (DHT) and Δ(4)-TIB, but not MPA, stabilize AR protein levels, initiate specific AR intramolecular interactions critical for AR transcriptional regulation, and increase proliferation of AR positive MDA-MB-453 breast cancer cells. Structural modeling and molecular dynamic simulation indicate that Δ(4)-TIB induces a more stable AR structure than does DHT, and MPA a less stable one. Microarray expression analyses confirms that the molecular actions of Δ(4)-TIB more closely resembles DHT in breast cancer cells than either ligand does to MPA.
Dame Roma Mitchell Cancer Research Laboratories, The University of Adelaide and Hanson Institute, Australia.
Tina
T
Bianco-Miotto
Dame Roma Mitchell Cancer Research Laboratories, The University of Adelaide and Hanson Institute, Australia; Cancer Biology Group, Basil Hetzel Institute for Translational Health Research, The University of Adelaide, Australia.
Andrew P
AP
Trotta
Cancer Biology Group, Basil Hetzel Institute for Translational Health Research, The University of Adelaide, Australia.
Eleanor F
EF
Need
Dame Roma Mitchell Cancer Research Laboratories, The University of Adelaide and Hanson Institute, Australia.
Alice M C
AM
Lee
Dame Roma Mitchell Cancer Research Laboratories, The University of Adelaide and Hanson Institute, Australia.
Aleksandra M
AM
Ochnik
Cancer Biology Group, Basil Hetzel Institute for Translational Health Research, The University of Adelaide, Australia.
Lauren
L
Giorgio
Cancer Biology Group, Basil Hetzel Institute for Translational Health Research, The University of Adelaide, Australia.
Damien A
DA
Leach
Cancer Biology Group, Basil Hetzel Institute for Translational Health Research, The University of Adelaide, Australia.
Erin E
EE
Swinstead
Cancer Biology Group, Basil Hetzel Institute for Translational Health Research, The University of Adelaide, Australia.
Melissa A
MA
O'Loughlin
Dame Roma Mitchell Cancer Research Laboratories, The University of Adelaide and Hanson Institute, Australia.
Michelle R
MR
Newman
Department of Surgery, Flinders Medical Centre, Bedford Park, Adelaide, SA, Australia.
Stephen N
SN
Birrell
Dame Roma Mitchell Cancer Research Laboratories, The University of Adelaide and Hanson Institute, Australia.
Lisa M
LM
Butler
Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Qld, Australia.
Jonathan M
JM
Harris
Dame Roma Mitchell Cancer Research Laboratories, The University of Adelaide and Hanson Institute, Australia; Cancer Biology Group, Basil Hetzel Institute for Translational Health Research, The University of Adelaide, Australia. Electronic address: grant.buchanan@adelaide.edu.au.
Grant
G
Buchanan
D000728:Androgens / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001711:Biotransformation; D045744:Cell Line, Tumor; D013196:Dihydrotestosterone / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D017258:Medroxyprogesterone Acetate / Q000737:chemistry / Q000494:pharmacology; D056004:Molecular Dynamics Simulation; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009650:Norpregnanes / Q000378:metabolism; D009652:Norpregnenes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D013329:Structure-Activity Relationship
C529843:3beta-OH-tibolone; C410798:AR protein, human; D000728:Androgens; D009363:Neoplasm Proteins; D009650:Norpregnanes; D009652:Norpregnenes; D011944:Receptors, Androgen; C485706:delta(4)-tibolone; D013196:Dihydrotestosterone; D017258:Medroxyprogesterone Acetate
Androgen receptor; Coactivators; Medroxyprogesterone acetate; Molecular models; Progestins; Testosterone