At the time I was diagnosed (2004), there was enough research on the 'new' estrogen receptor [ERbeta], to cause concern.
At diagnosis, ERbeta has generally become downregulated. In contrast, ERalpha, which is otherwise restricted to stromal cells, starts to appear in PCa (epithelial) cells. This is therefore an early event, whereas the androgen receptor [AR] is unchanged (wild-type) until it has become a target of treatment.
That's what prompted me to control estradiol (target = 20 pg/mL) and to experiment with high-normal testosterone. This was in early-2006, after failed surgery/salvage radiation & before any other treatment.
In the new study, following prostatectomy, tissue was tested for ER alpha and ERbeta (ERα and ERβ)."
The patients with ERα(-)/ERβ(+) staining results had significantly fewer {biochemical recurrences} than other patients ...
"... patients with ERα(-)/ERβ(+) PCa also had a significantly lower risk of recurrence ...
"In the survival analysis, the 5-year {biochemical recurrence}-free survival rate of patients with ERα(-)/ERβ(+) PCa was higher than that of other patients (85.7 vs. 66.1% ...).
"Excluding the effects of well-studied risk factors for recurrence .., the present study showed that ERα and ERβ have prognostic value for non-metastatic PCa.
"The 5-year {biochemical recurrence}-free survival rate is significantly higher in patients whose PCa tissue has ERα(-)/ERβ(+) staining results."
Nothing surprising here to those familiar with studies going back twenty years. ERα is growth promoting, whereas ERβ resists growth.
However, estradiol continues to be ignored by doctors. Dr. Myers denied that it had any importance. Morgentaler seems to have ignored it.
While men who are ERα(-)/ERβ(+) at diagnosis have an edge, I think that it might mostly mean that they were diagnosed early. As I understand it, loss of ERβ is almost inevitable.
For ERα to drive progression, estradiol [E2] is clearly important. The AR is important too - growth will not occur if there is no testosterone. PCa cells that have ERα, can create the estradiol needed to activate it - from testosterone, via the aromatase enzyme. Aromatase has no role in cells until ERα appears.
High-normal testosterone may be able resist E2, but this will depend on having some ERβ. The natural ligand for ERβ is a metabolite of dihydrotestosterone [DHT].
While the new paper is only of passing interest to most (if at all), I have posted because mention of estrogen receptors in male tissue is so rare.
It is not quite accurate to say that "growth will not occur if there is no testosterone." In fact, although bicalutamide will prevent LNCaP from growing, bicalutamide plus physiological levels of estradiol allows LNCaP to grow at maximum speed. See: pubmed.ncbi.nlm.nih.gov/753... Also, although normal prostate epithelial cells have almost no ER-alpha activity, 94% of CRPC does. See: ncbi.nlm.nih.gov/pmc/articl... Finally, high local levels of estradiol binding to ER-alpha is what causes prostate cancer in the first place. See: ncbi.nlm.nih.gov/pubmed/180...
Unfortunately, too many doctors are totally ignorant of this last fact because it was published in one of the most prestigious biological journals in the world and was never published in any medical journal.
Seeing your name took me right back to Sammy's group, such a long time ago.
The Castagnetta/Carruba paper you mentioned was recently cited (2020) [1]:
"... not all in vitro PCa models are appropriate to study ER functions, but they have still been inconsistently used in this context. For example, it has been known for decades that LNCaP cells—the most widely used human PCa model—have a mutated AR that can be activated by E2 in addition to androgens46,47and have low, if any, expression of both ERs 48,49. Nevertheless, several groups used this model to study E2 impact on PCa cell proliferation and survival 50–52."
Your explanation would make perfect sense if E2 were given to LNCaP in an environment devoid of T and bicalutamide. However, in the experiment I cited, E2 was given to LNCaP in an environment where biculatamide was given. Although biculatamide is known to block iAR so that T does not bind to it, to say that the Castagnetta paper was due to E2 binding to iAR is to say that E2 binds to iAR much more strongly than biculatamide (or T) does. Also, long ago I found an article that claimed that the amount of ER-alpha in LNCaP varied greatly depending on the exact environment that was used to maintain the LNCaP cells, but unfortunately, I did not save that link...
So far, nobody has produced any evidence to dispute that ER-alpha is essential for the start of PCa (high local levels of E2 cause mutation and mitosis in normal prostate epithelial cells) and that as PCa gets more aggressive, in general there is a higher proportion of PCa that exhibits ER-alpha activity, until you get to CRPC, where 94% exhibit ER-alpha activity.
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