Molecular and structural basis of androgen receptor responses to dihydrotestosterone, medroxyprogesterone acetate and δ4-tibolone

Tina Bianco-Miotto, Andrew P. Trotta, Eleanor F. Need, Alice M C Lee, Aleksandra M. Ochnik, Lauren Giorgio, Damien A. Leach, Erin E. Swinstead, Melissa A. O'Loughlin, Michelle R. Newman, Stephen N. Birrell, Lisa M. Butler, Jonathan M. Harris, Grant Buchanan

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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 (δ4-TIB) that has both androgenic and progestagenic properties. Here, we show that 5α-dihydrotestosterone (DHT) and δ4-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 δ4-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 δ4-TIB more closely resembles DHT in breast cancer cells than either ligand does to MPA.

LanguageEnglish
Pages899-908
Number of pages10
JournalMolecular and Cellular Endocrinology
Volume382
Issue number2
DOIs
Publication statusPublished - 15 Feb 2014

Keywords

  • Androgen receptor
  • Coactivators
  • Medroxyprogesterone acetate
  • Molecular models
  • Progestins
  • Testosterone

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology

Cite this

Bianco-Miotto, Tina ; Trotta, Andrew P. ; Need, Eleanor F. ; Lee, Alice M C ; Ochnik, Aleksandra M. ; Giorgio, Lauren ; Leach, Damien A. ; Swinstead, Erin E. ; O'Loughlin, Melissa A. ; Newman, Michelle R. ; Birrell, Stephen N. ; Butler, Lisa M. ; Harris, Jonathan M. ; Buchanan, Grant. / Molecular and structural basis of androgen receptor responses to dihydrotestosterone, medroxyprogesterone acetate and δ4-tibolone. In: Molecular and Cellular Endocrinology. 2014 ; Vol. 382, No. 2. pp. 899-908.
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abstract = "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 (δ4-TIB) that has both androgenic and progestagenic properties. Here, we show that 5α-dihydrotestosterone (DHT) and δ4-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 δ4-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 δ4-TIB more closely resembles DHT in breast cancer cells than either ligand does to MPA.",
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Bianco-Miotto, T, Trotta, AP, Need, EF, Lee, AMC, Ochnik, AM, Giorgio, L, Leach, DA, Swinstead, EE, O'Loughlin, MA, Newman, MR, Birrell, SN, Butler, LM, Harris, JM & Buchanan, G 2014, 'Molecular and structural basis of androgen receptor responses to dihydrotestosterone, medroxyprogesterone acetate and δ4-tibolone', Molecular and Cellular Endocrinology, vol. 382, no. 2, pp. 899-908. https://doi.org/10.1016/j.mce.2013.11.002

Molecular and structural basis of androgen receptor responses to dihydrotestosterone, medroxyprogesterone acetate and δ4-tibolone. / Bianco-Miotto, Tina; Trotta, Andrew P.; Need, Eleanor F.; Lee, Alice M C; Ochnik, Aleksandra M.; Giorgio, Lauren; Leach, Damien A.; Swinstead, Erin E.; O'Loughlin, Melissa A.; Newman, Michelle R.; Birrell, Stephen N.; Butler, Lisa M.; Harris, Jonathan M.; Buchanan, Grant.

In: Molecular and Cellular Endocrinology, Vol. 382, No. 2, 15.02.2014, p. 899-908.

Research output: Contribution to journalArticle

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AU - Bianco-Miotto, Tina

AU - Trotta, Andrew P.

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AU - Ochnik, Aleksandra M.

AU - Giorgio, Lauren

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AU - O'Loughlin, Melissa A.

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