Page 75 - Read Online

Page 252 Thomas et al. J Transl Genet Genom 2024;8:249-77 https://dx.doi.org/10.20517/jtgg.2024.15

keratinization of the epithelium, as well as neoplasia in the prostate of adult rodent models [37-39] , studies have
also shown the administration of estrogen-induced BPH in dogs. Moreover, the estrogenic effect has been
demonstrated to induce aberrations in the prostatic epithelium in both primates and humans [39,40] .
Therefore, maintaining the estrogen/testosterone (E/T) ratio is integral for maintaining normal function
and homeostasis of the prostate gland . Besides androgens and estrogens, progesterone, prolactin (a
[39]
[2]
hypophyseal hormone), and insulin regulate prostatic function and growth .
Steroid action in the prostate gland is mediated through respective intracellular hormone receptors. The
human prostate expresses AR, estrogen receptors α and β (ERα and ERβ), estrogen-responsive G protein-
coupled receptor 30 (GPR30), progesterone receptor (PR), and glucocorticoid receptor (GR) . Following
[2]
puberty, the steady state phase of the prostate gland is maintained by balancing cell proliferation and cell
[41]
death, a process regulated by AR signaling in both the epithelium and stromal cells of the prostate . During
the prenatal and postnatal differentiated stage, ERα is primarily expressed in the stroma and smooth muscle
cells, while ERβ is expressed in the epithelium [42-44] . The compartmentalization of expression and the
differential affinity of both ERα and β to bind to ligands and cofactors suggests the diverse functional role of
estrogen within the prostate gland. Experiments in mice show that ERα-regulated transcription of cytokine
genes in the mesenchyme regulates prostate differentiation and morphology during development.
Meanwhile, estrogen-mediated signaling in the prostate epithelium, mediated via ERβ, has been shown to be
important for epithelial function .
[39]
Isoforms of PR (PRA and PRB) are predominantly expressed in the stromal and smooth muscle cells of the
prostate. The interaction with the prostate epithelium is crucial for PR expression in the stromal cells.
Notably, PR activation has been observed to inhibit stromal expansion, which contrasts ERα regulation of
stromal cells . These observations suggest the coordinated activity of PR and ERα in maintaining
[45]
epithelium-stromal homeostasis in the prostate gland; however, the mechanisms remain unclear.
Glucocorticoids exert pleiotropic effects systemically through the GR receptors. In the prostate, GR and AR
share overlapping cistromes and transcriptomic signatures. AR activation has been shown to downregulate
GR expression in the prostate epithelium, indicating a critical negative feedback regulation between these
two hormone receptors. Consequently, in castration conditions, GR signaling can bypass AR inhibition,
[46]
promoting therapeutic resistance and prostate cancer cell survival .

IMMUNE LANDSCAPE IN PROSTATE GLAND
Tumor-infiltrating immune cells influence the progression of prostate cancer and its response to treatment,
yet understanding the immune microenvironment crucial for normal prostate function remains limited.
Recent studies utilizing bulk and single-cell sequencing techniques on normal and non-cancerous prostate
tissue have identified a diverse array of leukocytes, including mononuclear phagocytes (MNPs), mast cells,
natural killer (NK) cells, B cells, and tissue-resident T cells. Cross-species analysis in mice has revealed that
T cells and MNPs, which persist even in prostate cancer, primarily populate the healthy prostate. Cross-
analyses of single-cell RNA sequencing datasets in humans have identified six distinct classes of MNPs in
the normal prostate, including monocytes, conventional dendritic cells (cDC1 and cDC2 subsets),
proliferating macrophages, and various macrophage subclasses, including MAC1, MAC2, and
MAC-MT [47,48] .

Tissue-resident macrophages are crucial during embryonic development and in maintaining adult tissue
homeostasis . The diversity observed among MNPs within the prostate suggests potential tissue-specific
[49]
functions. Transcriptomic analyses reveal that certain macrophage subclasses, such as MAC-MT, are
exclusive to the prostate gland and exhibit heightened expression of zinc transporter genes, implicating their