androgen deprivation therapy ͉ testosterone ͉ TGF␤1 ͉ metastasis E arly studies suggested that the prostatic epithelial androgen receptor (AR), when activated by androgens, increased cellular proliferation (1, 2). Clinical studies also pointed out that androgen deprivation therapy (ADT) with suppression of androgens/AR functions, is an effective treatment for most prostate cancer patients (3, 4). However, most prostate tumors regrow after 12-18 months of continuous ADT (1-4). The detailed mechanisms of why suppression of androgens/AR ultimately fails and cancers recur as a more aggressive type and metastasize remain unclear.The conventional concept of the AR role in prostate cancer is to promote cancer progression, and positive AR staining can be found in many prostate tumors even at the later stages. In addition to androgens, other factors could also affect AR activity, such as (a) AR mutations or amplification, (b) changes in AR and AR coregulators interactions, or (c) growth factors/kinases signal pathways that activate AR activity at the castration level of androgen (1-4). However, why patients receiving ADT tended to have an earlier development of more aggressive types of cancer and whether AR has a differential role in different prostatic cells and/or in different prostate cancer stages remain unclear.Here, we report the generation of a mouse cancer model lacking the AR only in its prostatic epithelium (pes-ARKO-TRAMP), which develops prostate cancer spontaneously with an intact immune system. Notably, through AR gain-and loss-of-function in epithelial-stromal cell coculture and coimplantation experiments, we demonstrated that the AR could function in epithelial basal intermediate cells as a tumor suppressor to suppress prostate cancer metastasis, in epithelial luminal cells as a surviving factor, and in stromal cells as a proliferator to stimulate cancer progression. These contrasting data challenge the currently used ADT that systematically suppresses androgen actions, and thus reduces both proliferative and suppressor functions of AR. Our results suggest the need for better therapies that only target the proliferative function of AR.

Cutaneous wounds heal more slowly in elderly males than in elderly females, suggesting a role for sex hormones in the healing process. Indeed, androgen/androgen receptor (AR) signaling has been shown to inhibit cutaneous wound healing. AR is expressed in several cell types in healing skin, including keratinocytes, dermal fibroblasts, and infiltrating macrophages, but the exact role of androgen/AR signaling in these different cell types remains unclear. To address this question, we generated and studied cutaneous wound healing in cell-specific AR knockout (ARKO) mice. General and myeloid-specific ARKO mice exhibited accelerated wound healing compared with WT mice, whereas keratinocyte-and fibroblast-specific ARKO mice did not. Importantly, the rate of wound healing in the general ARKO mice was dependent on AR and not serum androgen levels. Interestingly, although dispensable for wound closure, keratinocyte AR promoted re-epithelialization, while fibroblast AR suppressed it. Further analysis indicated that AR suppressed wound healing by enhancing the inflammatory response through a localized increase in TNF-α expression. Furthermore, AR enhanced local TNF-α expression via multiple mechanisms, including increasing the inflammatory monocyte population, enhancing monocyte chemotaxis by upregulating CCR2 expression, and enhancing TNF-α expression in macrophages. Finally, targeting AR by topical application of a compound (ASC-J9) that degrades AR protein resulted in accelerated healing, suggesting a potential new therapeutic approach that may lead to better treatment of wound healing.

Upon insult, such as infection or tissue injury, the innate and adaptive immune systems initiate a series of responses to defend the body. Recent studies from immune cell-specific androgen receptor (AR) knockout mice demonstrated that androgen and its receptor (androgen/AR) play significant roles in both immune regulations. In the innate immunity, androgen/AR is required for generation and proper function of neutrophils; androgen/AR also regulates wound healing processes through macrophage recruitment and proinflammatory cytokine production. In adaptive immunity, androgen/AR exerts suppressive effects on development and activation of T and B cells. Removal of such suppression causes thymic enlargement and excessive export of immature B cells. Altogether, androgen/AR plays distinct roles in individual immune cells, and targeting androgen/AR may help in treatment and management of immune-related diseases.

Neutrophils, the major phagocytes that form the first line of cell-mediated defense against microbial infection, are produced in the bone marrow and released into the circulation in response to granulocyte-colony stimulating factor (G-CSF). Here, we report that androgen receptor knockout (ARKO) mice are neutropenic and susceptible to acute bacterial infection, whereas castration only results in moderate neutrophil reduction in mice and humans. Androgen supplement can restore neutrophil counts via stabilizing AR in castrated mice, but not in ARKO and testicular feminization mutant (Tfm) mice. Our results show that deletion of the AR gene does not influence myeloid lineage commitment, but significantly reduces the proliferative activity of neutrophil precursors and retards neutrophil maturation. CXCR2-dependent migration is also decreased in ARKO neutrophils as compared with wild-type controls. G-CSF is unable to delay apoptosis in ARKO neutrophils, and ARKO mice show a poor granulopoietic response to exogenous G-CSF injection. In addition, AR can restore G-CSF–dependent granulocytic differentiation upon transduction into ARKO progenitors. We further found that AR augments G-CSF signaling by activating extracellular signal-regulated kinase 1/2 and also by sustaining Stat3 activity via diminishing the inhibitory binding of PIAS3 to Stat3. Collectively, our findings demonstrate an essential role for AR in granulopoiesis and host defense against microbial infection.

To differentiate roles of androgen receptor (AR) in prostate stromal and epithelial cells, we have generated inducible-(ind)ARKO-TRAMP and prostate epithelial-specific ARKO TRAMP (pes-ARKO-TRAMP) mouse models, in which the AR was knocked down in both prostate epithelium and stroma or was knocked out in the prostate epithelium, respectively. We found that loss of AR in both mouse models resulted in poorly differentiated androgen deprivation therapy ͉ testosterone ͉ TRAMP