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Androgens Inhibit the Stimulatory Action of 17β-Estradiol on Normal Human Breast Tissue in Explant Cultures.

Eigeliene, Natalija; Elo, Teresa; Linhala, Mari; Hurme, Saija; Erkkola, Risto and Härkönen, Pirkko LU (2012) In Journal of Clinical Endocrinology and Metabolism 97(7). p.1116-1127
Abstract
Background: The data concerning the effects and safety of androgen in human breast tissue are conflicting.



Objective: Our aim was to analyze the effects of androgens on normal human breast tissue (HBT).



Approach: We cultured explants of HBT (obtained from reduction mammoplasty operations of postmenopausal women) with or without testosterone (T) and 5α-dihydrotestosterone (DHT) or in combination with 17β-estradiol (E(2)) for 7 and 14 d to study the effects of androgens on proliferation, apoptosis, target gene expression, and steroid receptors. The androgen receptor (AR) and estrogen receptor (ER) dependences of the effects were studied with the antihormones bicalutamide and fulvestrant,... (More)
Background: The data concerning the effects and safety of androgen in human breast tissue are conflicting.



Objective: Our aim was to analyze the effects of androgens on normal human breast tissue (HBT).



Approach: We cultured explants of HBT (obtained from reduction mammoplasty operations of postmenopausal women) with or without testosterone (T) and 5α-dihydrotestosterone (DHT) or in combination with 17β-estradiol (E(2)) for 7 and 14 d to study the effects of androgens on proliferation, apoptosis, target gene expression, and steroid receptors. The androgen receptor (AR) and estrogen receptor (ER) dependences of the effects were studied with the antihormones bicalutamide and fulvestrant, respectively.Results:The hormone responsiveness of cultured breast tissue was assessed by assaying apolipoprotein-D and prostate-specific antigen expression increased by androgens and amphiregulin and trefoil factor-1 expression induced by E(2) treatment. T and DHT reduced proliferation and increased apoptosis in breast epithelium, the effects of which were reversed by bicalutamide. In combination with E(2), they suppressed E(2)-stimulated proliferation and cell survival. DHT also inhibited basal (P < 0.05) and E(2)-induced expression of cyclin-D1 mRNA (P < 0.05). Immunohistochemistry showed that T (P < 0.05) and DHT (P < 0.05) increased the relative number of AR-positive cells, whereas ERα-positive (P < 0.001) cell numbers were strongly decreased. The percentage of ERβ-positive cells remained unchanged. E(2) treatment increased ERα-positive (P < 0.01) cells, whereas AR- (P < 0.05) and ERβ-expressing (P < 0.001) cells diminished. These effects were repressed in combination cultures of E(2) with T and DHT.



Conclusion: T and DHT inhibited proliferation and increased apoptosis in the epithelium of cultured normal HBT and opposed E(2)-stimulated proliferation and cell survival in an AR-dependent manner. These effects were associated with changes in the proportions of ERα- and AR-positive epithelial cells. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Clinical Endocrinology and Metabolism
volume
97
issue
7
pages
1116 - 1127
publisher
The Endocrine Society
external identifiers
  • wos:000306286100005
  • pmid:22535971
  • scopus:84863597131
ISSN
1945-7197
DOI
10.1210/jc.2011-3228
language
English
LU publication?
yes
id
507a9d12-2050-4ec0-9cea-4c4a6093a25c (old id 2519009)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/22535971?dopt=Abstract
date added to LUP
2012-05-07 11:41:53
date last changed
2017-08-20 04:06:48
@article{507a9d12-2050-4ec0-9cea-4c4a6093a25c,
  abstract     = {Background: The data concerning the effects and safety of androgen in human breast tissue are conflicting.<br/><br>
<br/><br>
Objective: Our aim was to analyze the effects of androgens on normal human breast tissue (HBT).<br/><br>
<br/><br>
Approach: We cultured explants of HBT (obtained from reduction mammoplasty operations of postmenopausal women) with or without testosterone (T) and 5α-dihydrotestosterone (DHT) or in combination with 17β-estradiol (E(2)) for 7 and 14 d to study the effects of androgens on proliferation, apoptosis, target gene expression, and steroid receptors. The androgen receptor (AR) and estrogen receptor (ER) dependences of the effects were studied with the antihormones bicalutamide and fulvestrant, respectively.Results:The hormone responsiveness of cultured breast tissue was assessed by assaying apolipoprotein-D and prostate-specific antigen expression increased by androgens and amphiregulin and trefoil factor-1 expression induced by E(2) treatment. T and DHT reduced proliferation and increased apoptosis in breast epithelium, the effects of which were reversed by bicalutamide. In combination with E(2), they suppressed E(2)-stimulated proliferation and cell survival. DHT also inhibited basal (P &lt; 0.05) and E(2)-induced expression of cyclin-D1 mRNA (P &lt; 0.05). Immunohistochemistry showed that T (P &lt; 0.05) and DHT (P &lt; 0.05) increased the relative number of AR-positive cells, whereas ERα-positive (P &lt; 0.001) cell numbers were strongly decreased. The percentage of ERβ-positive cells remained unchanged. E(2) treatment increased ERα-positive (P &lt; 0.01) cells, whereas AR- (P &lt; 0.05) and ERβ-expressing (P &lt; 0.001) cells diminished. These effects were repressed in combination cultures of E(2) with T and DHT.<br/><br>
<br/><br>
Conclusion: T and DHT inhibited proliferation and increased apoptosis in the epithelium of cultured normal HBT and opposed E(2)-stimulated proliferation and cell survival in an AR-dependent manner. These effects were associated with changes in the proportions of ERα- and AR-positive epithelial cells.},
  author       = {Eigeliene, Natalija and Elo, Teresa and Linhala, Mari and Hurme, Saija and Erkkola, Risto and Härkönen, Pirkko},
  issn         = {1945-7197},
  language     = {eng},
  number       = {7},
  pages        = {1116--1127},
  publisher    = {The Endocrine Society},
  series       = {Journal of Clinical Endocrinology and Metabolism},
  title        = {Androgens Inhibit the Stimulatory Action of 17β-Estradiol on Normal Human Breast Tissue in Explant Cultures.},
  url          = {http://dx.doi.org/10.1210/jc.2011-3228},
  volume       = {97},
  year         = {2012},
}