Prostate Cancer & Hormones - Estrogen... - Advanced Prostate...

Advanced Prostate Cancer

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Prostate Cancer & Hormones - Estrogen [2] - Discovery of ERbeta.

7 years ago•3 Replies

In my earlier post, I argued that estradiol [E2] & testosterone [T] seem to pull in different directions, & that an E2:T imbalance in men has been noted in a number of diseases.

[1] Estrogen Receptors.

The importance of the androgen receptor [AR] in PCa therapy is well known. We try to starve it of androgen & precursor hormones & attack it directly with AR antagonists, & yet it mostly continues to be a key player when treatment fails. The AR is still the target of interest 70 years after Huggins castrated his first dogs.

With such an obvious villain (AR, not Huggins -LOL), & with a monotherapy mindset, there has been little interest in estrogen & its receptors.

[1a] It has only been 20 years since Jan-Åke Gustafsson of the Karolinska Institute, Sweden, reported the existence of a novel estrogen receptor [ER] in rat ovary & prostate. He named it ERbeta to distinguish it from "classical" ER - which became ERalpha.

[1b] (2001 - Italy)

"The present study shows that the ERbeta gene is expressed together with ERalpha in normal prostates ... whereas it is barely detectable in prostate cancer ..."

[1c] (2001 - Australia - with Gustafsson)

"Five normal prostates from organ donors and 159 radical prostatectomy specimens from patients with clinically localized PC were assessed for ERbeta expression ..."

"All of the five normal prostates showed strong ERbeta-nuclear staining in >95% of the epithelium and 35% of the stromal cells. The number of ERbeta-positive cases declined to 24.2% (38/157) in hyperplasia adjacent to carcinoma and 11.3% (18/159) in PCs."

Note that it was already known that ERalpha was confined to stromal cells in normal prostates. So by 2001, we have this picture of ERalpha in the stroma & ERbeta in the epithelium (where cancer occurs), & a loss of ERbeta as PCa develops. Was it possible the ERbeta had a protective role against stromal ERalpha, acting in a paracrine fashion?

[1d] (2003 - Sweden - Gustafsson)

"Our understanding of estrogen signaling has undergone a true paradigm shift over recent years, following the discovery in 1995 of a second estrogen receptor, estrogen receptor beta (ERbeta). In many contexts ERbeta appears to antagonize the actions of ERalpha (yin/yang relationship) although there also exist genes that are specifically regulated by one of the two receptors. Studies of ERbeta knockout mice have shown that ERbeta exerts important functions in the ovary, central nervous system, mammary gland, prostate gland, hematopoiesis, immune system, vessels and bone. The use of ERbeta-specific ligands against certain forms of cancer represents one of the many pharmaceutical possibilities that have been created thanks to the discovery of ERbeta."

[1e] (2003 - Germany - Bonkoff)

{In parallel with Gustafsson, Bonhoff had been doing important ER-PCa research.}

"The present review gives a survey on the differential expression of estrogen receptors alpha and beta (ERalpha, ERbeta) and the progesterone receptor (PR) in human prostate tissue and discusses their potential implications for normal and abnormal prostatic growth. The differentiation compartment of the prostatic epithelium (secretory luminal cells) expresses high levels of ERbeta, while the ERalpha is restricted to the proliferation compartment (basal cells). In high-grade prostatic intraepithelial neoplasia (HGPIN), ERalpha gene expression extends to luminal cells and thus may mediate cancerogenic effects of estrogens on the dysplastic epithelium. Conversely, the ERbeta is downregulated in HGPIN indicating that the chemopreventive effects of phytoestrogens mediated by the ERbeta are partially lost. Irrespective of grades and stages, prostate cancer retains high levels of the ERbeta, which is partially lost in androgen-insensitive stages of the disease. In contrast with breast cancer, the presence of the ERalpha and the progesterone receptor (PR) is a late event in prostate cancer progression. At least 30% of metastatic and androgen-insensitive tumors express high levels of the PR indicating that these tumors harbor a functional ERalpha."

In other words, a disturbing development in PCa, is the loss or ERbeta in affected epithelial cells & the emergence of ERalpha.

Now, consider that at diagnosis, AR is usually quite normal. The AR changes that subsequently occur are a result of ADT. The changes occurring to the ERalpha:beta balance seem to have been met with a huge yawn in important research centers.

When a patient asked about the role of estrogen in PCa, Dr. Myers said that there was no role.

Dr Morgentaler has his famous model where AR is saturated with T at fairly low levels (I believe <250 ng/dL). High T levels cannot make PCa grow any faster once saturation has been attained. Estrogen has no place in this model. A high E2 (>30 pg/mL) coupled with low T (<350 ng/dL) - i.e. estrogen dominance - is not viewed as dangerous.

[1f] (2004 - France)

"The characterization of estrogen receptor beta (ERbeta) brought new insight into the mechanisms underlying estrogen signaling. Estrogen induction of cell proliferation is a crucial step in carcinogenesis of gynecologic target tissues, and the mitogenic effects of estrogen in these tissues (such as breast, endometrium and ovary) are well documented both in vitro and in vivo. There is also an emerging body of evidence that colon and prostate cancer growth is influenced by estrogens. In all of these tissues, most studies have shown decreased ERbeta expression in cancer as compared with benign tumors or normal tissues, whereas ERalpha expression persists."

"Numerous clinical and in vitro studies suggest that imbalanced ERα/ERβ expression is a common feature and could be a critical step of estrogen dependent tumor progression. ERβ seems to play a key role in the mitogenic action of estrogen by providing protection against ERα-induced hyperproliferation. A role in apoptosis might also be possible."

[1g] (2004 - China)

"The expression of ERalpha and ERbeta was analysed in 32 cases of PCa, 12 cases of normal prostate tissue and 32 cases of benign prostate hyperplasia (BPH)"

"Compared with the tissue of BPH, the ERalpha expression significantly increased, but the ERbeta expression decreased in the tissue of PCa... Compared with in the early stage and high differentiation of prostatic carcinoma, the ERalpha expression increased obviously, but ERbeta expression decreased in the developed stage and low differentiation"

[1h] (2004 - Sweden)

"Estrogens have previously been extensively used in prostate cancer treatment. Serious side effects, primarily in cardiovascular system have, however, limited their use. The therapeutic effect of estrogen in preventing prostate cancer growth was mainly obtained indirectly by feedback inhibition of the hypothalamic release of LRH leading to lowered serum androgen levels and castration like effects. Prostate tissue is also most probably a target for direct regulation by estrogens. Prostate contains estrogen receptor alpha (ERalpha) and beta (ERbeta), which are localized characteristically in stroma and epithelium, respectively. The physiological function of these receptors is not known but there is evidence of the role of estrogens in prostatic carcinogenesis."

"Prolonged treatment of adult rodents with estrogens along with androgens ... leads to epithelial metaplasia, PIN-like lesions and even adenocarcinoma of prostate speaking for the role of estrogen in prostate cancer development. Recent results concerning antiestrogen inhibition of prostate cancer development beyond PIN-type lesions in transgenic mouse models further suggests a role for estrogens in prostate cancer progression. These results also suggest that direct inhibition of estrogen action at the level of prostate tissue may provide an important novel principle of development of prostate cancer therapies."

[1i] (2005 - Sweden - Gustafsson)

"We have known for many years that estrogen is more than the female hormone. It is essential in the male gonads, and in both sexes, estrogen has functions in the skeleton and central nervous system, on behavior, and in the cardiovascular and immune systems. An important aspect of the discovery of estrogen receptor (ER) beta is that the diverse functions of estrogen can now be divided into those mediated by ERalpha and those mediated by ERbeta. Pharmacological exploitation of this division of the labors of estrogen is facilitated by the ligand-binding specificity and selective tissue distribution of the two ERs. Because the ligand binding domains of ERalpha and ERbeta are significantly different from each other, selective ligands can be (and have been) developed to target the estrogenic pathway that is malfunctioning, without interfering with the other estrogen-regulated pathways. Because of the absence of ERbeta from the adult pituitary and endometrium, ERbeta agonists can be used to target ERbeta with no risk of adverse effects from chemical castration and uterine cancer. Some of the diseases in which there is hope that ERbeta agonists will be of benefit are prostate cancer, autoimmune diseases, colon cancer, malignancies of the immune system, and neurodegeneration."

[1j] (2006 - Italy)

"Prostate cancer is a major health issue in westernized countries, being considered a prototypical age-related, androgen-dependent tumor. However, data on the association between circulating androgens and prostate cancer have been inconsistent and mostly not compatible with the androgen hypothesis. In addition, plasma androgen-to-estrogen ratio appears to decrease with age, suggesting that estrogens may also have a role. Results from our own and others' studies suggest that circulating steroids cannot be considered representative of their actual intraprostatic levels. This is a consequence of the expression and/or activity of steroid enzymes, including 17beta-hydroxysteroid dehydrogenase (17beta-HSD), 5alpha-reductase, 3alpha/3beta-HSD, and aromatase, which may eventually lead to a differential tissue accumulation of steroid derivatives having distinct biological activities. Interestingly, many of the genes encoding for steroid enzymes are highly polymorphic in nature, although only a few studies have investigated their relation with prostate cancer and the data presently available are inconclusive. Locally produced or metabolically transformed estrogens may differently affect proliferative activity of prostate cancer cells. In our studies, estrogen may either stimulate or decrease prostate cancer cell growth, also depending on the receptor status. In particular, an imbalance of ERalpha and ERbeta expression may be critical to determine the ultimate estrogen effects on prostate cancer cell growth. Furthermore, evidence is accumulating that estrogens regulate gene transcription through an array of estrogen-response elements (EREs) and non-EREs, either ligand-dependent or -independent. This is further complicated by the presence of receptor isoforms, distinct cofactor interaction, and potential heterodimerization. Based on this combined evidence, a hypothetical model of prostate cancer progression is presented."

[1k] (2007 - Italy)

"Prostate cancer is the commonest non-skin cancer in men. Incidence and mortality rates of this tumor vary strikingly throughout the world. Although several factors have been implicated to explain this remarkable variation, lifestyle and dietary factors may play a dominant role, with sex hormones behaving as intermediaries between exogenous factors and molecular targets in development and progression of prostate cancer. Human prostate cancer is generally considered a paradigm of androgen-dependent tumor; however, estrogen role in both normal and malignant prostate appears to be equally important. The association between plasma androgens and prostate cancer remains contradictory and mostly not compatible with the androgen hypothesis. Similar evidence apply to estrogens, although the ratio of androgen to estrogen in plasma declines with age. Apart from methodological problems, a major issue is to what extent circulating hormones can be considered representative of their intraprostatic levels. Both nontumoral and malignant human prostate tissues and cells are endowed with key enzymes of steroid metabolism, including 17betahydroxysteroid dehydrogenase (17betaHSD), 5beta-reductase, 3alpha/3betaHSD, and aromatase. A divergent expression and/or activity of these enzymes may eventually lead to a differential prostate accumulation of steroid derivatives having distinct biological activities, as it occurs for hydroxylated estrogens in the human breast. Locally produced or metabolically transformed estrogens may differently affect proliferative activity of prostate cancer cells. Aberrant aromatase expression and activity has been reported in prostate tumor tissues and cells, implying that androgen aromatization to estrogens may play a role in prostate carcinogenesis or tumor progression."

...

I will break off here, having reviewed the literature up to 2007.

Amusing to end with Carruba's observation:

"The association between plasma androgens and prostate cancer remains contradictory and mostly not compatible with the androgen hypothesis."

There are no U.S. papers in this post. Research interest was mostly elsewhere (at least up to 2007).

... to be continued.

-Patrick

[1a] ncbi.nlm.nih.gov/pubmed/865...

[1b] ncbi.nlm.nih.gov/pubmed/113...

[1c] ncbi.nlm.nih.gov/pubmed/114...

[1d] onlinelibrary.wiley.com/doi...

[1e] ncbi.nlm.nih.gov/pubmed/146...