Estrogen action: a historic perspective on the implications of considering alternative approaches - PubMed (original) (raw)

Review

Estrogen action: a historic perspective on the implications of considering alternative approaches

Elwood V Jensen et al. Physiol Behav. 2010.

Abstract

In the 50 years since the initial reports of a cognate estrogen receptor (ER), much has been learned about the diverse effects and mechanisms of estrogens, such as 17beta-estradiol (E(2)). This expert narrative review briefly summarizes perspectives and/or recent work of the authors, who have been addressing different aspects of estrogen action, but take a common approach of using alternative considerations to gain insight into mechanisms with clinical relevance, and inform future studies, regarding estrogen action. Their "Top Ten" favorite alternatives that are discussed herein are as follows. 1 - E(2) has actions by binding to a receptor that do not require its enzymatic conversion. 2 - Using a different strategy for antibody binding could make the estrogen receptor (ER) more discernible. 3 - Blocking ERs, rather than E(2) production, may be a useful strategy for breast cancer therapy. 4 - Secretion of alpha-fetoprotein (AFP), rather than only levels of E(2) and/or progesterone, may influence breast cancer risk. 5 - A peptide derived from the active site of AFP can produce the same benefits of the entire endogenous protein in endocrine cancers. 6 - Differential distribution of ER subtypes in the body and brain may underlie specific effects of estrogens. 7 - ERbeta may be sufficient for the trophic effects of estrogen in the brain, and ERalpha may be the primary target of trophic effects in the body. 8 - ERbeta may play a role in the trophic effects of androgens, and may also be relevant in the periphery. 9 - Downstream of E(2)'s effects at ERbeta, there may be consequences for biosynthesis of progestogens and/or androgens. 10 - Changes in histones and/or other factors, which may be downstream of ERbeta, potentially underlie the divergent effects of E(2) in the brain and peripheral tissues.

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Figures

Fig. 1

Top: A cartoon representation of the apparatus that was utilized to tritiate estradiol. Bottom: Graph below demonstrates the amount of radioactivity (dpm; as a measure of tissue sensitivity to estradiol) in various organs (uterus, vagina, liver, kidney, blood, muscle) up to 16 hours after injection of tritiated estradiol. Based upon results reported in [2,3].

Fig. 2

Top: Schematic of estrogen binding to antibody and receptor. Bottom: Immunocytochemistry examples of how estrogen receptor (ER) antibody was utilized to stain ER expression in mammary tumor tissue, with the sample on the left having low ER immunoreactivity (“ER poor”) and the sample on the right have more ER immunoreactivity (“ER rich”).

Fig. 3

Depiction of typical rates of estrogen receptor (ER) rich or ER poor breast cancer. This information was then used to put patient on endocrine and/or chemotherapy. A better outcome was demonstrated for those who had ER rich breast cancer with endocrine therapy. However, a question remained on how to treat the ~12% of patients who have ER rich tumors, but do not respond to endocrine therapy.

Fig. 4

Tumor volumes following α-fetoptotein (AFP) peptide treatment (AFPep) in two animal models of breast cancer (carcinogen-induced cancer model in rats (A) and MCF-7 tumor xenograft model in mice (B). In both cases, volumes of tumors across groups at the end of the experiment were reduced by administration of AFPep compared to vehicle (* p<0.05). Based upon results reported in [52,53].

Fig. 5

Tumor (A) and uterine (B) wet weight (mean ± sem) of rats that were administered placebo vehicle, estradiol (E2), or an ERα-SERM (propyl pyrazole triol- PPT), or an ERβ-SERM (diarylpropionitrile- DPN) once a week for 14 weeks. E2 and PPT increased these weights compared to vehicle (* p<0.05).

Fig. 6

Anxiety behavior in the elevated plus maze (A) of rats administered placebo vehicle, estradiol (E2), or an ERα-SERM (propyl pyrazole triol- PPT), or an ERβ-SERM (diarylpropionitrile- DPN). E2 and DPN increased time spent on the open arms of the elevated plus maze compared to vehicle (* P<0.05). Circles indicate plasma levels of 3α,5α-THP (mean ± sem). Western blot showing representative bands (B) of the 5α-reductase type 1 enzyme, and the loading control β-actin, in the hippocampus of rats treated with vehicle, PPT, E2, or DPN. E2 and DPN increase expression of 5α-reductase in these samples.

Fig. 7

Cognitive performance of adult female mice (genetic knockouts for ERβ- KO; or their wildtype-WT counterparts) administered placebo vehicle, 17β-estradiol (E2), or diarylpropionitrile (DPN). E2 and DPN enhanced performance in this task of WT, but not KO, mice, compared to vehicle administration (* P<0.05). Circles indicate hippocampus levels of 3α,5α-THP in mice. KO mice have lower levels of 3α,5α-THP in the hippocampus than do WT mice after administration of E2 or DPN. Based upon results reported in [111].

Fig. 8

Some of the potential mechanisms, in the cell itself (A) or via metabolism to other neuroactive sterods (B), of estradiol (E2) for its functional effects. E2 can have classic effects to bind to estrogen receptors (ERs), such as ERα and ERβ, and have transcriptional activity. E2 may interact with binding proteins, such as α-foteptrotein (AFP). E2 may also interact with other membrane receptors, such as an ER (which may potentiate intracellular ER function), G-protein coupled receptors (GPCRs), growth factors, and/or neurotransmitter systems, which may involve activation of signal transduction pathways (e.g. adenosine 3′,5′-monophosphate- cAMP, protein kinase A- PKA, phospholipase C- PLC, protein kinase C- PKC, mitogen activating protein kinase- MAPK, extracellular signal-regulated kinase- ERK1/2). E2's functional effects through ERβ may be via altering steroid metabolism of progestogens and androgens.

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Estrogen action: a historic perspective on the implications of considering alternative approaches - PubMed (original) (raw)