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

doi:10.1016/j.mce.2013.11.002

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

Blood Cancer Program

Research output: Contribution to journal › Article › peer-review

3 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.

Original language	English
Pages (from-to)	899-908
Number of pages	10
Journal	Molecular and Cellular Endocrinology
Volume	382
Issue number	2
DOIs	https://doi.org/10.1016/j.mce.2013.11.002
Publication status	Published or Issued - 15 Feb 2014

Keywords

Androgen receptor
Coactivators
Medroxyprogesterone acetate
Molecular models
Progestins
Testosterone

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Endocrinology

Access to Document

10.1016/j.mce.2013.11.002

Cite this

Bianco-Miotto, T., Trotta, A. P., Need, E. F., Lee, A. M. C., Ochnik, A. M., Giorgio, L., Leach, D. A., Swinstead, E. E., O'Loughlin, M. A., Newman, M. R., Birrell, S. N., Butler, L. M., Harris, J. M., & Buchanan, G. (2014). Molecular and structural basis of androgen receptor responses to dihydrotestosterone, medroxyprogesterone acetate and δ⁴-tibolone. Molecular and Cellular Endocrinology, 382(2), 899-908. https://doi.org/10.1016/j.mce.2013.11.002

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

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.",

keywords = "Androgen receptor, Coactivators, Medroxyprogesterone acetate, Molecular models, Progestins, Testosterone",

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

note = "Funding Information: This work was funded by the Australian Research Council (GB DP110101101) and the Prostate Cancer Foundation of Australia (GB PG2210). TBM was supported by a National Health and Medical Research Council Peter Doherty Fellowship (349556). EFN holds a Hospital Research Foundation Early Career Fellowship. LMB was supported by a senior research fellowship from the Cancer Council of South Australia. The authors would like to thank Associate Professor Christine Clarke and Dr Dinny Graham (Westmead Institute for Cancer Research, University of Sydney) for providing pVA3-Luc. Ms Joanna Gillis provided technical assistance. Δ 4 -TIB was kindly provided by Merck. ",

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doi = "10.1016/j.mce.2013.11.002",

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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

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T1 - Molecular and structural basis of androgen receptor responses to dihydrotestosterone, medroxyprogesterone acetate and δ4-tibolone

AU - Bianco-Miotto, Tina

AU - Trotta, Andrew P.

AU - Need, Eleanor F.

AU - Lee, Alice M C

AU - Ochnik, Aleksandra M.

AU - Giorgio, Lauren

AU - Leach, Damien A.

AU - Swinstead, Erin E.

AU - O'Loughlin, Melissa A.

AU - Newman, Michelle R.

AU - Birrell, Stephen N.

AU - Butler, Lisa M.

AU - Harris, Jonathan M.

AU - Buchanan, Grant

N1 - Funding Information: This work was funded by the Australian Research Council (GB DP110101101) and the Prostate Cancer Foundation of Australia (GB PG2210). TBM was supported by a National Health and Medical Research Council Peter Doherty Fellowship (349556). EFN holds a Hospital Research Foundation Early Career Fellowship. LMB was supported by a senior research fellowship from the Cancer Council of South Australia. The authors would like to thank Associate Professor Christine Clarke and Dr Dinny Graham (Westmead Institute for Cancer Research, University of Sydney) for providing pVA3-Luc. Ms Joanna Gillis provided technical assistance. Δ 4 -TIB was kindly provided by Merck.

PY - 2014/2/15

Y1 - 2014/2/15

N2 - 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.

AB - 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.

KW - Androgen receptor

KW - Coactivators

KW - Medroxyprogesterone acetate

KW - Molecular models

KW - Progestins

KW - Testosterone

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