New study below [1].
The trouble with Charles Huggins castration therapy of 1941, which looks as though it will be around in 2041, is that not only is it not a cure, but it has led to an obsession with the androgen receptor [AR]. Most of the alterations that occur in the AR are not due to the natural progression of the cancer, but rather as responses to treatment. The AR is often quite normal at diagnosis.
What isn't normal at diagnosis is estrogen receptor [ER] balance.
In a young healthy prostate we expect to find ERalpha in stroma cells & ERbeta in epithelial cells. ERalpha is pro-growth, whereas ERbeta is growth-resistant. By the time that PCa is emerging in the epithelium, ERbeta is being replaced by ERalpha. And yet there is very little interest in this fact.
Or in the fact that our estradiol:testosterone ratio [E2:T] is much higher than it was decades earlier.
If there is little interest in E2, there is virtually no interest in progesterone.
The presence of the progesterone receptor [PR] in stromal cells has been known for several decades.
From 2001, Bonkoff (Germany):
"The recent discovery of the classical estrogen receptor alpha (ERalpha) in metastatic and recurrent prostatic adenocarcinoma suggests that estrogens are implicated in prostate cancer progression."
"To get more insight into estrogen signaling in prostate cancer tissue, the current study has examined the immunoprofile of the estrogen-inducible progesterone receptor (PR), and evaluated its relation to ERalpha gene expression."
"In primary tumors, the PR was detectable in 36% of primary Gleason grade 3 (5 of 14 cases), 33% of primary Gleason grade 4 (5 of 15 cases), and in 58% of primary Gleason grade 5 tumors (7 of 12 cases). None of the 41 primary tumors investigated revealed significant PR expression in more than 50% of tumor cells. Conversely, moderate to strong receptor expression was observed in 60% of metastatic lesions (9 of 15 cases), and in 54% of androgen-insensitive tumors (38 of 71 cases). Irrespective of grades and stages, the presence of the PR was invariably associated with high steady state levels of ERalpha mRNA ..."
"The progressive emergence of the PR during tumor progression obviously reflects the ability of metastatic and androgen-insensitive tumors to use estrogens through a ERalpha-mediated pathway. The present data provide a theoretical background for studying the efficiency of antiestrogens and antigestagens in the medical treatment of advanced prostate cancer."
...
Mifepristone is a steroidal antiprogestogen that acts as a competitive progesterone receptor antagonist. [3]
Check (2010) had the crazy idea to try it out on male mice with male cancers [4]:
"Eight-week-old mice with a strong predisposition to testicular or prostate cancer were gavaged with mifepristone. Olive oil was used in place of mifepristone in order to provide a control. Survival rates and body conditioning scores were compared after one year of treatment."
"... data support the hypothesis that various cancers may utilize a mechanism that is present in normal pregnancy that involves secretion of a progesterone-induced protein that blocks natural killer cell activity. The hypothesis that the cancer cells have the capacity to direct local progesterone production is supported by demonstrating the benefit of a progesterone receptor antagonist in tumors restricted to males."
...
Grindstat (2015), Norway, reported [5]:
"In univariate analyses, high tumor cell density ... and high tumor stromal cell density level ... of progesterone receptor were both significantly associated with tumor progression and clinical failure. In multivariate analysis, progesterone receptor expression in tumor cells was an independent negative prognostic factor for clinical failure (HR: 2.5 ...)."
The new study is a follow-up:
"The role of steroid hormones in carcinogenesis of the prostate is to some extent unraveled thorough the effect of androgen deprivation therapy on prostate cancer (PCa) progression. Other members of the steroid hormone family, such as progesterone, are also implicated in PCa, but progesterone's role remains undefined. This study aimed to examine the distribution of progesterone receptor isoforms (PGRA, PGRB) in PCa tissue and their association with clinical endpoints. This was conducted retrospectively by collecting radical prostatectomy specimens from 535 patients. Tissue was analyzed using tissue microarray, where representative tumor areas were carefully selected. ... Herein, we discovered a solely stromal PGRA- and a stromal and epithelial PGRB expression. Further, a high PGRB expression in tumor tissue was associated with an unfavorable prognosis in both univariate and multivariate analyses: Biochemical failure (HR: 2.0 ...) and clinical failure (HR: 2.5 ...)"
...
Abiraterone acetate (Zytiga) inhibits CYP17A1 & thus prevents the conversion of pregnenolone and progesterone to downstream steroid hormones. Presumably, this leaves one with a surfeit of pregnenolone and progesterone. Might not be relevant, but it's worth noting.
-Patrick
[1] ncbi.nlm.nih.gov/pubmed/300...
[2] ncbi.nlm.nih.gov/pubmed/115...
[3] en.wikipedia.org/wiki/Mifep...
New, Non-hormonal Target Identified for Advanced Prostate Cancer
