Androgen Receptor and Cancer


androgensOne of the subjects I investigated during the past weeks is the role of androgen in cancer. Androgen receptors (AR) blockage is a treatment strategy used in e.g. prostate cancer, in order to stop or reduce cancer progression. However, as you will see from the papers cited below, and these are just a few out of a large number of publications on this subject, the androgen receptor has a very important role in tumor progression and its blocking alone may lead to cancer cell death in many tumor types.

I actually believe that just like for every problem there are multiple ways to solve it, hormones is one of the angles that is relevant for all cancers capturing a solution to every type of cancer. The difficulty is that there are so many hormones in the human body, interconnected like a spider web. However, beyond this complexity, it has been shown that e.g. thyroid hormones, and more specifically T4 (inhibition) may hold the answer to many types of cancers. (Ref.).

The high relevance of hormones for the human body is undebatable since hormones may even define who we are, how we think and how we look. At cellular level, hormones have impact on mayble all intracellular mechanisms, controlling even the membrane proton pumps such as Na/H exchange (Ref.), pumps that are highly relevant in cancers (Ref.).

Back to androgen receptors, I like the idea of focusing on AR blockage because that can be done relatively easy with various FDA approved drugs that have a well known safety profile. Wouldn’t be great if with one single and safe pill taken every day we could eliminate cancer? As you will see in the references below, that actually happened in patients with e.g. adrenal tumor and breast tumor. I am sure that if I search I will find many more case reports but the references below are enough to demonstrate the concept.

Relevant References and Case Reports in Humans:

Androgen Receptor as a Driver of Therapeutic Resistance in Advanced Prostate Cancer

Androgen receptor-blocking agents: potential role in pancreatic cancer Confirmatory evidence has now come from a double-blind, placebo-controlled trial in patients with pancreatic cancer in which flutamide, the pure androgen receptor blocker, doubled survival duration over control patients.

Androgens Up-regulate the Insulin-like Growth Factor-I Receptor in Prostate Cancer Cells Agents targeting these signaling pathways (ERK ) or the IGF-IR itself should therefore be considered as a complement of standard anti-androgen therapy to induce tumor regression and possibly reduce the chance or delay the time of tumor progression to androgen independence.

The androgen receptor as an emerging target in hepatocellular carcinoma

Androgen receptor signaling regulates growth of glioblastoma multiforme in men.

Complete Response of Metastatic Androgen Receptor–Positive Breast Cancer to Bicalutamide: Case Report and Review of the Literature Approximately 10% to 32% of TNBC have androgen receptor (AR) expression.

Multiple Molecular Subtypes of Triple-Negative Breast Cancer Critically Rely on Androgen Receptor and Respond to Enzalutamide In Vivo Our study indicates that multiple subtypes of AR+ TNBC depend on AR for proliferation, migration, and invasion, and tumor growth in vivo and provides promising preclinical data on the efficacy of enzalutamide in TNBC with low AR expression.

Vitamin D and androgen receptor-targeted therapy for triple-negative breast cancer. Surprisingly, we found that AR antagonists inhibited proliferation of most BC cell lines in an AR-independent manner, raising questions regarding their mechanism of action. As VDR agonist they used Calcitriol.

Disappearance of a virilizing adrenal tumor following therapy with cyproterone acetate. As the patient refused surgery, virilization was treated with the antiandrogen cyproterone acetate (CPA), but for only 4 months because clinical and hormone abnormalities reversed and the tumor was no longer visible. The patient remains symptom-free. This first report of a curative effect of CPA on a purely virilizing adrenal tumor opens new avenues in the management of such tumors.

Androgen receptor inducing bladder cancer progression by promoting an epithelial-mesenchymal transition. It is concluded that suppression of AR expression decreased the production of TGF-β, inhibiting EMT and bladder cancer cell growth in vitro and in vivo, implying that its use might be a potential therapeutic target for the treatment of bladder cancer.

Source and Dose:

One example of AR blocker is Cyproterone Acetate, a substance that is also used in contraceptive pills. Cyproterone Acetate is cheap and available in most countries via local or online pharmacies. Some online pharmacies are selling it even without prescription. The dose that is typically used for contraceptive pills is in the range of a few mg/day while that used to block androgen receptors is in the range of 10 to 200mg/day. Because Cyproterone Acetate can also lead to some toxicity on the liver, I would prefer to stay in the 50mg/day dose range but you would need to check with your doctor.

Note that besides, Cyproterone Acetate there are many other androgen receptor blocking drugs commercially available. (Ref.) Even Cimetidine (an anti histamine safe drug that is a must in my view for every cancer patient to reduce chance for metastasis) seems to have anti androgen activity (Ref.).

However, in some cases, androgen receptor blockers may not be enough (Ref.). In that case, to have an effective treatment strategy, we may need to also reduce androgen production. This is typically done with drugs such as Ketokonazole, Abiraterone Acetate, etc. that reduce hormone production by inhibiting relevant enzymes at cellular level but also with GnRH modulators (discussed in an earlier post on this website) that lead to inhibition of the circulating hormones (released from the brain) and that in turn trigger the androgen production in adrenals and reproductive glands. Indeed, GnRH modulators alone are used by some clinics to treat various tumor types (Ref.).


Androgens such as testosterone are synthesized primarily by the Leydig cells in the testes, under the regulation of luteinizing hormone (LH) produced by the anterior pituitary gland. LH secretion is in turn regulated by gonadotropin-releasing hormone (GnRH). Once produced, testosterone mostly circulates in the blood bound to serum sex hormone-binding globulin (SHBG) and albumin (Ref.)

Androgen Receptor blockers are also used in the treatment of hirsutism and other androgen-dependent conditions and as a component of hormone replacement therapy for transgender women. The drugs act as selective antagonists of the androgen receptor (AR), preventing androgens like testosterone and dihydrotestosterone (DHT) from binding to and activating the AR and exerting their biological effects in the body.

However, besides testosterone and dihydrotestosterone pathways, androgen receptors are facilitating many other cellular processes in the human body, of which some are very relevant to cancer development:

Transcription_Androgen Receptor nuclear signaling:

Source for the above figure:

Other References:

Dual targeting of androgen receptor and mTORC1 by salinomycin in prostate cancer

Androgen receptor (AR) and PI3K/AKT/mTORC1 are major survival signals that drive prostate cancer to a lethal disease. Reciprocal activation of these oncogenic pathways from negative cross talks contributes to low/limited success of pathway-selective inhibitors in curbing prostate cancer progression. We report that the antibiotic salinomycin, a cancer stem cell blocker, is a dual-acting AR and mTORC1 inhibitor, inhibiting PTEN-deficient castration-sensitive and castration-resistant prostate cancer in culture and xenograft tumors. AR expression, its transcriptional activity, and androgen biosynthesis regulating enzymes CYP17A1, HSD3β1 were reduced by sub-micro molar salinomycin. Estrogen receptor-α expression was unchanged. Loss of phosphorylated AR at serine-81, which is an index for nuclear AR activity, preceded total AR reduction. Rapamycin enhanced the AR protein level without altering phosphoAR-Ser81 and CYP17A1. Inactivation of mTORC1, evident from reduced phosphorylation of mTOR and downstream effectors, as well as AMPK activation led to robust autophagy induction. Apoptosis increased modestly, albeit significantly, by sub-micro molar salinomycin. Enhanced stimulatory TSC2 phosphorylation at Ser-1387 by AMPK, and reduced inhibitory TSC2 phosphorylation at Ser-939/Thr-1462 catalyzed by AKT augmented TSC2/TSC1 activity, which led to mTORC1 inhibition. AMPK-mediated raptor phosphorylation further reduced mTOR’s kinase function and mTORC1 activity. Our novel finding on dual inhibition of AR and mTORC1 suggests that salinomycin is potentially active as monotherapy against advanced prostate cancer.

Androgen receptor: structure, role in prostate cancer and drug discovery

Androgens and androgen receptors (AR) play a pivotal role in expression of the male phenotype. Several diseases, such as androgen insensitivity syndrome (AIS) and prostate cancer, are associated with alterations in AR functions. Indeed, androgen blockade by drugs that prevent the production of androgens and/or block the action of the AR inhibits prostate cancer growth. However, resistance to these drugs often occurs after 2–3 years as the patients develop castration-resistant prostate cancer (CRPC). In CRPC, a functional AR remains a key regulator. Early studies focused on the functional domains of the AR and its crucial role in the pathology. The elucidation of the structures of the AR DNA binding domain (DBD) and ligand binding domain (LBD) provides a new framework for understanding the functions of this receptor and leads to the development of rational drug design for the treatment of prostate cancer. An overview of androgen receptor structure and activity, its actions in prostate cancer, and how structural information and high-throughput screening have been or can be used for drug discovery are provided herein.


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7 thoughts on “Androgen Receptor and Cancer

    1. Thank you for your msg Carl! I do my best to share whenever I can and I am happy to hear that you appreciate that.
      There is so much I would like to write on so many subjects … just that the challenges at home next to my full time job, takes sometimes all my time.

    1. Yes Meech, although the testosterone is not inhibited by cyproterone-like drugs its receptors will and that will come with the low testosterone related side effects. Ketokonazole-like drugs will also lead to that (in high doses) but it will lower other hormones as well as it acts on an enzyme earlier in the pathway of the hormone production. Other drugs such as cholesterol lowering drugs (e.g. statins) may produce same kind of effects although lower in amplitude.

  1. Hi Daniel
    Take a look at some of the research by people such as Dr Abraham Morgentaler from Harvard, or Dr John Lee, on the effect of low testosterone on prostate cancer. They argue that low T has an adverse effect – hence it is usually older men that get prostate cancer. Dr Morgentaler has recently given a talk on this, in Europe. It should be on his website or you tube. I would be interested to hear your thoughts on this.

    1. Hi Aaron,

      Thank you for your comment. I need to have a closer look at the subject to be able to give you an informed answered.
      For now I give you just a feeling: the answer may be related to the difference in action between testosterone (T) and dihydrotestosterone (DHT). T is converted in DHT by 5 alfa – reductase enzyme (5AR) in the prostate cells:
      Dihydrotestosterone (DHT) which is chemically=Testosterone+2 hydrogens, is five times more potent that testosterone in driving cancer.

      Indeed, it seems that man with congenital deficiency of 5AR have low levels of DHT, a diminutive prostate, and complete lack of prostatic glandular epithelium and are notable for a lack of reported cases of adenocarcinoma of the prostate.

      DHT acts on the skin, sometimes producing acne, and on the hair follicles, putting hair on the chest but often taking it off the scalp. Indeed, it was found that men with bald spots at the top of their heads (vertex baldness) were one and a half times more likely to have prostate cancer than those without bald spots.

      So my feeling is that an answer may be found in 5AR which may increase its expression at older age (reference needed). If that is the case, at older age DHT will increase and lead to an increased chance for prostate cancer. On this line, you could argue that it is not Testosterone but its metabolite that is the problem.

      If what dr. Morgentaler is showing is true than Testosterone injections may help reduce the chance for prostate cancer. I would have a wild explanation for that in the following way: injected T, will lead to reduced production of T in the prostate cancer cells (which also have the capability to produce testosterone via a feedback loop leading to reduction of LH. In this way there will be lower or no T and therefore DHT produced in the prostate cancer cells leading to decrease or stop in the proliferation.

      If I would test this route of treatment (i.e. T injections) than I would start with low dose and probably add a 5AR inhibitor ( just to make sure I would reduce the chance for the conversion of injected T into DHT.

      One other relevant reference on this line is here: “Cancer paradox: Testosterone injections combat lethal prostate tumors”

  2. There has been a lot of research on androgen receptors lately , not only for prostate cancer but also breast cancer and I´m quite surprised nobody commented about it yet.
    Dr Glaser published some interesting articles on her practice treating breast cancer with testosterone+aromatase inhibitors

    More on this subject can be easily found on google scholar

    Clinical trials focusing on the progesterone receptor also are currently in course, using an abortive drug that blocks the progesterone receptor called Mifepristone

    This study states that mifepristone may work even in types of cancer others than hormonal, independently from progesterone receptors.

    Other links focusing on antiprogestins and progesterone target treatment may be easily found also .

    I´ve been reading a lot on these subjects and amazes me how all this info is hidden from all breast cancer patients. it seems really promising and I´m currently trying to implement this on my mother´s treatment.

    There is some talk on estriol(E3) beeing useful also as an antiproliferative form of estrogen that binds preferably to the beta estrogen receptor in contrast to estradiol that binds preferably to alpha estrogen receptor . (being proliferative),This subject still lacks academic evidence but seems very interesting also.

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