Retinoic acid receptor–related orphan receptor γ (ROR-γ) & the Androgen Receptor (AR)

[pjoshea13]

New study below [1].  Don't be put off by the title.  

When I decided to methodically go through the PubMed PCa literature 12 years ago, I began with vitamins.  I can tell you that Vitamin A is the worst starting point.  Expecting a single receptor for retinol. I discovered that there was a retinoic acid receptor [RAR] & a retinoid X receptor [RXR] & that each come in three flavors [alpha, beta & gamma], & with up to four splice variants.

PCa causes a change in the expression (occurrence) of these, so it would appear that those that fade from view are the good guys & those whose expression is upregulated must be helpful to the cancer.  So I decided that vitamin A supplementation might not be wise.

When retinoic acid receptor–related orphan receptor γ (ROR-γ) cropped up, I'd had enough of the subject, but it might turn out to be important.

It seems that "ROR-γ is overexpressed and amplified in metastatic CRPC tumors, and that ROR-γ drives AR expression in the tumors".

"ROR-γ antagonists suppress the expression of both AR and its variant AR-V7 in prostate cancer (PCa) cell lines and tumors."

"ROR-γ antagonists suppressed tumor growth in multiple AR-expressing, but not AR-negative, xenograft PCa models, and they effectively sensitized CRPC tumors to enzalutamide, without overt toxicity, in mice."

Given that AR is still the main target in CRPC, & that every treatment meets resistance, the idea of an upstream therapy that removes AR from the picture is very attractive. 

For a friendlier account of the study & its implications, read:

medicalxpress.com/news/2016... 

-Patrick

[1]  nature.com/nm/journal/vaop/...

ROR-γ drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer

Junjian Wang,June X Zou,Xiaoqian Xue,Demin Cai,Yan Zhang,Zhijian Duan,Qiuping Xiang,Joy C Yang,Maggie C Louie,Alexander D Borowsky,Allen C Gao,Christopher P Evans,Kit S Lam,Jianzhen Xu,Hsing-Jien Kung,Ronald M Evans,Yong Xu& Hong-Wu Chen

AffiliationsContributionsCorresponding authors

Nature Medicine (2016) doi:10.1038/nm.4070

Received 31 December 2015 Accepted 19 February 2016 Published online 28 March 2016

Abstract

Abstract• Accession codes• References• Author information• Supplementary information

The androgen receptor (AR) is overexpressed and hyperactivated in human castration-resistant prostate cancer (CRPC). However, the determinants of AR overexpression in CRPC are poorly defined. Here we show that retinoic acid receptor–related orphan receptor γ (ROR-γ) is overexpressed and amplified in metastatic CRPC tumors, and that ROR-γ drives AR expression in the tumors. ROR-γ recruits nuclear receptor coactivator 1 and 3 (NCOA1 and NCOA3, also known as SRC-1 and SRC-3) to an AR–ROR response element (RORE) to stimulate AR gene transcription. ROR-γ antagonists suppress the expression of both AR and its variant AR-V7 in prostate cancer (PCa) cell lines and tumors. ROR-γ antagonists also markedly diminish genome-wide AR binding, H3K27ac abundance and expression of the AR target gene network. Finally, ROR-γ antagonists suppressed tumor growth in multiple AR-expressing, but not AR-negative, xenograft PCa models, and they effectively sensitized CRPC tumors to enzalutamide, without overt toxicity, in mice. Taken together, these results establish ROR-γ as a key player in CRPC by acting upstream of AR and as a potential therapeutic target for advanced PCa.   

[struwwellpeter]

So... no carrots?

[pjoshea13 in reply to struwwellpeter]

Hi Peter,

Carrots?  Eat your carrots but skip the beta-carotene supplement.

For preformed vitamin A, the only food to be wary of, I believe, is liver.  But I would eat it if someone cooked it for me (would a real friend really do that, though?)  

For provitamin A beta-carotene, food sources seem to be OK - although I would stay clear of carrot juice.

The study that killed beta-carotene as a supplement was the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study among 29,133 Finnish male smokers aged 50–69 years.  The beta-carotene-only arm (20 mg) had more PCa.  {+22%} 

In the 18-Year Post-Intervention Follow-Up study [1] (2014):

"Relative prostate cancer mortality was significantly lower among recipients of α-tocopherol than among nonrecipients {-16%}, whereas it was significantly higher among recipients of β-carotene than among nonrecipients {+20%}."

That statement looks to be misleading.  There were 4 arms to the study.  At the end of the study, the arm receiving both supplements showed no excess PCa risk.  The vitamin E had apparently protected the men from the beta carotene.  In the 18-year follow-up, they should have shown the beta-carotene risk split by those who took vitamin E & those who didn't.

In the cutely-named CARET study (Carotene and Retinol Efficacy Trial) [2], no excess PCa was reported for 30 mg β-carotene.  However, in men who took a daily supplement in addition to the CARET supplement:

"a relative risk for aggressive prostate cancer (Gleason ≥ 7 or stage III/IV) of {+52%}"

I can't believe I used a beta carotene supplement for twenty years!

Both intervention studies were intended to prevent lung cancer in smokers, so there is the question as to how the findings might translate to non-smpkers.

-Patrick

[1]  ncbi.nlm.nih.gov/pmc/articl...

[2]  ncbi.nlm.nih.gov/pmc/articl...

[chascri]

Once again you are flying above my head. Can you dumb it down for me. Your knowledge and research are impressive and I would like to know what you are saying. Laymen's summary in plain English please.😊

[pjoshea13]

The gist is that we have a potential target that is upstream of the androgen receptor [AR].  The focus has always been on the AR, either by denying it the androgen it needs for activation, or attacking it directly.  Going upstream to where problems start seems to be a departure.

-Patrick