Prostate cancer is the second most prevalent cancer in males in the United States. Standard therapy relies on removing, or blocking the actions of, androgens. In most cases, this therapy results in a regression of the cancer because the prostate and most primary prostate tumors depend on androgens for growth and the avoidance of apoptosis. However, a portion of the cancers eventually relapse, at which point they are termed "androgen refractory" and can no longer be cured by conventional therapy of any type. The precise molecular events that lead from androgen-sensitive prostate cancer to androgen-refractory prostate cancer are, therefore, of great interest. This review seeks to identify specific molecular events that may be linked directly to the progression to androgen-refractory cancer. Some of the mechanisms appear to involve the androgen receptor (AR) directly and include mutations in, or amplification of, the AR gene in a manner that allows the AR to respond to low doses of androgens, other steroids, or antiandrogens. In a less direct manner, coactivators may increase the sensitivity of the AR to androgens and even other nonandrogenic substances through a number of mechanisms. Additional indirect mechanisms that do not result from mutation of the AR may involve activation of the AR by peptide growth factors or cytokines or may involve bypassing the AR entirely via other cellular pathways. Identification of the role of these mechanisms in the progression to androgen-refractory prostate cancer is critical for developing therapies capable of curing this disease.

There is now substantial evidence that overweight and/or obesity and/or weight gain are risk factors for the development of postmenopausal breast cancer. In addition, obesity and/or elevated body mass index at breast cancer diagnosis has a negative impact on prognosis for both premenopausal and postmenopausal women. Therefore, understanding the mechanism of how obesity affects the mammary tumorigenesis process is an important health issue. Elevated serum estrogen levels as well as enhanced local production of estrogen have been considered primary mediators of how increased body weight promotes breast cancer development in postmenopausal women. Here, we provide an overview of estrogen's relationship with both obesity and breast cancer as separate entities. Human and relevant preclinical studies are cited. In addition, other growth factors that may be involved in this relationship are considered.

Obesity is a risk factor for postmenopausal breast cancer. Adiponectin/Acrp30 is lower in obese individuals and may be negatively regulating breast cancer growth. Here we determined that five breast cancer cell lines, MDA-MB-231, MDA-MB-361, MCF-7, T47D, and SK-BR-3, expressed one or both of the Acrp30 receptors. In addition, we found that the addition of Acrp30 to MCF-7, T47D, and SK-BR-3 cell lines inhibited growth. Oestrogen receptor (ER) positive MCF-7 and T47D cells were inhibited at lower Acrp30 concentrations than ER-negative SK-BR-3 cells. Growth inhibition may be related to apoptosis since PARP cleavage was increased by Acrp30 in the ER-positive cell lines. To investigate the role of ER in the response of breast cancer cells to Acrp30, we established the MDA-ERa7 cell line by insertion of ER-a into ER-a-negative MDA-MB-231 cells. This line readily formed tumours in athymic mice and was responsive to oestradiol in vivo. In vitro, MDA-ERa7 cells were growth inhibited by globular Acrp30 while the parental cells were not. This inhibition appeared to be due to blockage of JNK2 signalling. These results provide information on how obesity may influence breast cancer cell proliferation and establish a new model to examine interactions between ER and Acrp30.

It is well recognized that obesity increases the risk of various cancers, including breast malignancies in postmenopausal women. Furthermore, obesity may adversely affect tumor progression, metastasis, and overall prognosis in both pre- and postmenopausal women with breast cancer. However, the precise mechanism(s) through which obesity acts is/are still elusive and this relationship has been the subject of much investigation and speculation. Recently, adipose tissue and its associated cytokine-like proteins, adipokines, particularly leptin and adiponectin, have been investigated as mediators for the association of obesity with breast cancer. Higher circulating levels of leptin found in obese subjects could be a growth-enhancing factor as supported by in vitro and preclinical studies, whereas low adiponectin levels in obese women may be permissive for leptin's growth-promoting effects. These speculations are supported by in vitro studies which indicate that leptin promotes human breast cancer cell proliferation while adiponectin exhibits anti-proliferative actions. Further, estrogen and its receptors have a definite impact on the response of human breast cancer cell lines to leptin and adiponectin. More in-depth studies are needed to provide additional and precise links between the in vivo development of breast cancer and the balance of adiponectin and leptin.

SUMMARY Defining specific cellular and molecular mechanisms in most obesity-related diseases remains an important challenge. Here we report a serendipitous finding that consumption of a high-fat diet (HFD) greatly increased the occurrence of skin lesions in C57BL/6 mice. We demonstrated that HFD induced the accumulation of a specific type of CD11c+ macrophages in skin preceding detectable lesions. These cells primed skin to induce IL-1β and IL-18 signaling, which further promoted the cytokines IFNγ- and IL-17-mediated skin inflammation. Mechanistically, epidermal fatty acid binding protein (E-FABP) was significantly upregulated in skin of obese mice, which coupled lipid droplet formation and NLRP3 inflammasome activation. Deficiency of E-FABP in obese mice decreased recruitment of CD11c+ macrophages in skin tissues, reduced production of IL-1β and IL-18, and consequently dampened activation of effector T cells. Furthermore, E-FABP deficient mice are completely resistant to HFD-induced skin lesions. Collectively, E-FABP represents a molecular sensor triggering HFD-induced skin inflammation.

Aims Recent studies in patients with cardiovascular diseases suggest potential for the use of orally administered l‐arginine, the precursor of nitric oxide, as a therapeutic agent. This crossover study was designed to examine the pharmacokinetics of single i.v. and oral doses of l‐arginine in healthy volunteers (n=10). Methods A preliminary control study (n=12) was performed to assess the variation in plasma l‐arginine concentrations when ingesting a normal diet. The observed variation was taken into account when interpreting the pharmacokinetic data obtained after exogenous administration. Results The mean baseline plasma concentration of l‐arginine in the control study was 15.1±2.6 μg ml−1. After intravenous administration (30 g over 30 min), the plasma concentration reached 1390±596 μg ml−1. The disappearance of l‐arginine appeared biphasic, with an initial rapid disappearance due to concentration‐dependent renal clearance followed by a slower fall in plasma concentrations due to nonrenal elimination. The peak concentration after oral administration (10 g) was 50.0±13.4 μg ml−1, occurring 1 h after administration. Renal elimination was not observed after oral administration of this dose. The absolute bioavailability of a single oral 10 g dose of l‐arginine is ≈20%. Conclusions This study provides basic knowledge of l‐arginine pharmacokinetics in healthy humans. Intravenous and oral administrations show at minimum a biphasic pattern. Further studies will assess whether a similar profile is observed when the drug is administered to patients.

Using differential display polymerase chain reaction, early growth response gene alpha (EGR alpha) was first isolated as a 291-base pair 3'-cDNA clone, which was highly expressed in the androgen-independent prostate carcinoma cell lines PC3 and DU145, as compared with the androgen-responsive prostate carcinoma cell line LNCaP. Full length cloning of the EGR alpha coding region revealed that EGR alpha was a new member of an important subfamily of nuclear zinc finger transcription factors (others members e.g. Sp1, EGR-2, and Wilms' tumor gene). Moreover, it was observed that EGR alpha, as with most Sp1 subfamily members, was conserved between mammalian species ranging from human to rabbit. Two hormones important for prostate development and differentiation were found to be potent regulators of EGR alpha mRNA expression. Androgens were observed to induce a down-regulation of EGR alpha mRNA expression (70% in 72 h), while epidermal growth factor induced a rapid transient up-regulation (6-fold in 100 min). The up-regulation was controlled at the transcriptional level and effectively blocked by staurosporine (which suggests the involvement of the protein kinase C pathway). Functional analysis demonstrated that EGR alpha could bind to, and stimulate transcription from, a basic transcription element (BTE) consensus sequence on DNA (BTE is a transcription-modulating sequence in the promoter region of some cytochrome P450 family members). Furthermore, in stage-synchronized prostate cells, EGR alpha mRNA was highly expressed in the early G1 phase of the cell cycle, similar to c-fos mRNA expression. These results indicated that the zinc finger transcription factor EGR alpha seems to play a role in cell cycle regulation.

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