DHEA can directly activate AR or ERβ in the prostatic epithelium or the AR or ERα in the prostatic stroma. DHEA can be a direct ligand for the AR in mutant prostate epithelial cells such as LNCaP and induce weak androgenic effects, potentially promoting prostate cancer growth, as shown by its stimulation of prostate cancer LNCaP cell proliferation, and modulation of cellular PSA, AR, ERβ, and IGF axis gene and protein expression, in a pattern similar to DHT and T, although on a lesser scale and delayed in time [18
ERβ is an important target in prostate[38
] for endogenous and exogenous estrogens and phytoestrogens and may play a role in modulating androgen activity. DHEA has been shown to exert direct agonist effects on ERβ as observed in competitive receptor binding assays, in which DHEA displayed a higher affinity for ERβ than for AR or ERα, with ERβ being the preferred target for the transcriptional effects of DHEA [39
Indirect effects refer to DHEA metabolism to androgenic ligands (including androstenedione, testosterone and DHT) or estrogenic ligands (including 7-OH-DHEA, 3β Adiol, or 17β estradiol). Receptors for DHEA or DHEAS have not been definitively isolated [40
]. DHEA sulfate (DHEAS) is present in high levels in the prostate, as is the sulfatase that converts DHEAS to DHEA [41
]. Prostate stromal and epithelial cells possess the enzymatic machinery to metabolize DHEA (intracrine) to more active androgenic and/or estrogenic steroids [1
] and express secondary mediators (paracrine) for epithelial growth and differentiation. Alternatively, DHEA metabolites may act on ERβ in the prostate, potentially antagonizing androgenic effects on prostate cancer growth. such as metabolism to 7α-hydroxy-DHEA (7HD), a known ligand for ERβ [44
The complexity of the balance between androgenic and estrogenic effects whether as direct ligands or metabolites of DHEA on the prostate is matched by the complexity of estrogen action through the ERα vs. ERβ. The intratissular balance of androgen and estrogen levels is most important for prostatic development and differentiation. Likewise, the balance between ERα and ERβ including the temporal and spatial expression determines response of prostate to estrogen and is crucial for prostate health [45
]. Estrogens have been long used in prostate cancer therapy and the role of estrogens in the prostate have been elegantly studied and reviewed [46
]. Estrogens have beneficial effects that support normal growth of the prostate but can also be detrimental to prostate growth and differentiation. [48
]. Estrogens acting through the prostate stromal ERα may be growth promoting while estrogens acting through the epithelial ERβ may be antagonistic to ERα-or AR-activated pathways [49
]. Excessive estrogen induces squamous metaplasia and can act synergistically with androgens to induce glandular hyperplasia. [51
]. To the contrary, estrogens can inhibit prostate cancer xenograft growth in female intact and ovariectomized mice, in the absence of androgens [52
]. These inhibitory effects were postulated to occur by direct actions via the ER or by E2
effects on other cells secreting secondary factors, which influence cancer cell growth. Additionally, ERβ knock-out mice exhibit increased epithelial proliferation compared with that observed in wild-type mice [53
] suggesting that ERβ may inhibit prostate growth.
What regulates the direction of estrogen action? What are downstream signal transduction pathways or gene effects of ER ligand/receptor complexes in either stromal cells or in epithelial cells? How do non-genomic effects of estrogen influence prostate functioning [54
]? Also beyond the scope of this discussion, what are effects of estrogens as converted to catechol estrogens which could react with DNA and lead to mutations initiating cancer [56
]? Paracrine functions become important when considering that stromal cells possess aromatase allowing conversion of testosterone to estrogens [57
]. Ellem and Risbridger propose a positive-feedback cycle where increased stromal aromatase production may increase local estrogens which then promote inflammation. The inflammation may further stimulate aromatase expression leading to progression of prostate cancer [59
]. In the context of reactive stroma, the relationship of reactive stroma to aromatase expression has not been validated.
A final possibility is that DHEA remains as a prohormone, and is not metabolized, at the increased levels over other steroids, provides a ‘hormonal buffer’ [60
] against endogenous androgen or estrogen levels.
In our studies aiming to determine downstream androgenic vs. estrogenic effects of DHEA, we evaluated the extent to which DHEA-modulated effects in LNCaP and LAPC-4 cells were mediated via the AR and/or ERβ. We found both receptors were involved. In both LNCaP and LAPC-4 prostate cancer cells, inhibitors of AR(Casodex) and ER (ICI 182,780) suppressed hormone-induced PSA mRNA and protein expression. These studies, in addition to others employing siRNAs to AR or ERβ, western blotting and confocal microscopic analyses, suggest that both AR and ERβ contribute to PSA expression induced by DHEA, DHT and E2 in LNCaP cells, and by DHT in LAPC-4 cells [61