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Many of the effects of estrogens on the uterus are mediated by ERalpha, the predominant ER in the mature organ. Because of the poor reproductive capacity of ERbeta knockout (BERKO) female mice (small litter size, multiple-resorbed fetuses), the role of uterine ERbeta was explored. In the immature uterus, ERalpha and ERbeta are expressed at comparable levels in the epithelium and stroma, and 17beta-estradiol (E(2)) treatment decreases ERbeta in the stroma. The immature uterus of untreated BERKO mice exhibits elevated levels of progesterone receptor (PR) and the proliferation-associated protein, Ki-67. It also exhibits exaggerated responsiveness to E(2), as indicated by enlargement of the lumen, increase in volume and protein content of uterine secretion, induction of the luminal epithelial secretory protein, complement C3, and its regulatory cytokine IL-1beta, and induction of vascular endothelial growth factor and insulin-like growth factor 1 but not its receptor. As expected, E(2) increased PR in the stroma and decreased it in the luminal epithelium of wild-type mice. In the BERKO uterus, E(2) induced PR in the stroma but did not down-regulate it in the epithelium. Increased cell proliferation and exaggerated response to E(2) in BERKO suggest that ERbeta plays a role in modulation of the effects of ERalpha and in addition (or as a consequence of this) has an antiproliferative function in the immature uterus.

In normal rats and mice, immunostaining with specific antibodies revealed that nuclei of most prostatic epithelial cells harbor estrogen receptor ␤ (ER␤). In rat ventral prostate, 530-and 549-aa isoforms of the receptor were identified. These sediment in the 4S region of low-salt sucrose gradients, indicating that prostatic ER␤ does not contain the same protein chaperones that are associated with ER␣. Estradiol (E2) binding and ER␤ immunoreactivity coincide on the gradient, with no indication of ER␣. In prostates from mice in which the ER␤ gene has been inactivated (BERKO), androgen receptor (AR) levels are elevated, and the tissue contains multiple hyperplastic foci. Most epithelial cells express the proliferation antigen Ki-67. In contrast, prostatic epithelium from wild-type littermates is single layered with no hyperplasia, and very few cells express Ki-67. Rat ventral prostate contains an estrogenic component, which comigrates on HPLC with the testosterone metabolite 5␣-androstane-3␤,17␤-diol (3␤Adiol). This compound, which competes with E 2 for binding to ER␤ and elicits an estrogenic response in the aorta but not in the pituitary, decreases the AR content in prostates of wild-type mice but does not affect the elevated levels seen in ER␤ knockout (BERKO) mice. Thus ER␤, probably as a complex with 3␤Adiol, is involved in regulating the AR content of the rodent prostate and in restraining epithelial growth. These findings suggest that ligands specific for ER␤ may be useful in the prevention and͞or clinical management of prostatic hyperplasia and neoplasia. E pidemiological and experimental studies indicate that estrogenic hormones are involved in both the induction and prevention of prostatic cancer (1-7), but their precise role is not well understood. Excessive exposure to estrogens during critical stages of development or long-term treatment of adult animals with estrogens or androgens leads to prostatic neoplasia (8, 9). In apparent contrast, diets rich in phytoestrogens, particularly soy products, are associated with a low risk of prostate cancer (10-12) and have chemopreventive properties in experimental tumor models (12, 13). Some of these conflicting observations may be explained by the fact that there are two distinct estrogen receptors, ER␣ and ER␤, which have unique and sometimes opposing roles (14). For example, recent studies have demonstrated that, in the rodent uterus, ER␤ acts to restrain the stimulatory action of ER␣ (15).Early studies, using both ligand-binding and immunochemical techniques, detected two types of estrogen-binding substances in human prostate (16), one of which is the classical estrogen receptor now known as ER␣. Low levels of this receptor are present in the stroma of rodent prostates, but none is detectable in the epithelium (17, 18). Because of this difference in the levels of this receptor, it was proposed that the effects of estrogen on the epithelium are indirect via an initial interaction with the stroma (18). But after the discovery of ER␤ in rat prostatic epithelium ...

Epidemiological evidence indicates that the association between body weight and breast cancer risk may differ across menopausal status as well as the estrogen receptor (ER) and progesterone receptor (PR) tumor status. To date, no meta-analysis has been conducted to assess the association between body weight and ER/PR defined breast cancer risk, taking into account menopausal status and study design. We searched MEDLINE for relevant studies published from January 1, 1970 through December 31, 2007. Summarized risk estimates with 95% confidence intervals (CIs) were calculated using a random-effects model. The summarized results of 9 cohorts and 22 case-control studies comparing the highest versus the reference categories of relative body weight showed that the risk for ER1PR1 tumors was 20% lower (95% CI ¼ 230% to 28%) among premenopausal (2,643 cases) and 82% higher (95% CI ¼ 55-114%) among postmenopausal (5,469 cases) women. The dose-response meta-analysis of ER1PR1 tumors showed that each 5-unit increase in body mass index (BMI, kg/m 2 ) was associated with a 33% increased risk among postmenopausal women (95% CI ¼ 20-48%) and 10% decreased risk among premenopausal women (95% CI ¼ 218% to 21%). No associations were observed for ER2PR2 or ER1PR2 tumors. For discordant tumors ER1PR2 (pre) and ER2PR1 (pre/post) the number of cases were too small (<200) to interpret results. The relation between body weight and breast cancer risk is critically dependent on the tumor's ER/PR status and the woman's menopausal status. Body weight control is the effective strategy for preventing ER1PR1 tumors after menopause. ' 2008 Wiley-Liss, Inc.Key words: breast cancer; body weight; body mass index; estrogen receptor; progesterone receptor; risk Obesity could affect breast cancer risk through affecting circulating endogenous estrogen levels. Therefore, it have been postulated that the association between body weight and breast cancer risk may be heterogeneous according to the tumor's estrogen receptor (ER) and progesterone receptor (PR) status. Cumulative epidemiological evidence 1-3 also suggests that the impact of body weight on breast cancer risk differs across women's menopausal status; studies indicate a weak inverse association between body weight and breast cancer risk among premenopausal women 4 and a positive association among postmenopausal women (reversal association discussion 5 ). 6Many epidemiological studies have evaluated body weight in relation to ER and PR defined breast cancer incidence. 10,20,21,26,30,32,37 One qualitative literature review 39 and one quantitative review 40 reported the relation of ER and/or PR defined breast cancer risk with postmenopausal obesity. However, no study has quantitatively summarized the results with a meta-analytical approach for the relationship between body weight and the risk of breast cancer defined by ER/PR status. We therefore summarized all available evidence to clarify the association between body weight and the incidence of breast cancer defined by ER/PR status of the tumo...

Immunohistochemical examination of ER-beta1 in addition to ER-alpha and PR is clinically important in patients with breast cancer treated with tamoxifen monotherapy. Further studies are needed to confirm our findings.

BACKGROUND Macrophages often infiltrate into solid tumor tissues. Tumor‐associated macrophages (TAMs) are known to play a crucial role in tumor progression. Monocyte chemoattractant protein‐1 (MCP‐1) is one of the major chemokines capable of inducing chemotactic migration of monocytes. METHODS With the objective of investigating the clinical significance of MCP‐1, the authors analyzed the expression of MCP‐1 and of some other molecules by immunohistochemistry in 230 samples of primary breast carcinoma tissue. MCP‐1 staining was performed using an anti‐MCP‐1 monoclonal antibody, and it was assessed by grading the percentage of stained cells. RESULTS It was found that 117 breast tumor specimens (51%) had intensive staining in tumor cells. The expression of MCP‐1 in tumor cells had a significant correlation with the expression of thymidine phosphorylase and membrane type 1‐matrix metalloproteinase. In addition, MCP‐1 expression tended to be associated with the accumulation of TAMs, which were counted by CD68 staining, and with microvessel density. MCP‐1 expression in TAMs was correlated significantly with the histologic vessel invasion of tumor cells. CONCLUSIONS The results of this study suggest that MCP‐1 may play key roles in macrophage recruitment, in the expression of angiogenic factors, and in the activation of matrix metalloproteinases in patients with breast carcinoma. Cancer 2001;92:1085–91. © 2001 American Cancer Society.

Histone deacetylase (HDAC) 6 is a subtype of the HDAC family; it deacetylates a-tubulin and increases cell motility. Here, we investigate the impact of an alteration of HDAC6 expression in estrogen receptor a (ER)-positive breast cancer MCF-7 cells, as we identified that HDAC6 is a novel estrogen-regulated gene. MCF-7 treated with estradiol showed increased expression of HDAC6 mRNA and protein and a four-fold increase in cell motility in a migration assay. Cell motility was increased to the same degree by stably transfecting the HDAC6 expression vector into MCF-7 cells. In both cases, the cells changed in appearance from their original round shape to an axon-extended shape, like a neuronal cell. This HDAC6 accumulation caused the deacetylation of a-tubulin. Either the selective estrogen receptor modulator tamoxifen (TAM) or the pure antiestrogen ICI 182,780 prevented estradiol-induced HDAC6 accumulation and deacetylation of a-tubulin, leading to reduced cell motility. Tubacin, an inhibitory molecule that binds to the tubulin deacetylation domain of HDAC6, also prevented estradiol-stimulated cell migration. Finally, we evaluated HDAC6 protein expression in 139 consecutively archived human breast cancer tissues by immunohistochemical staining. The prognostic analyses for these patients revealed no significant differences based on HDAC6 expression. However, subset analysis of ERpositive patients who received adjuvant treatment with TAM (n ¼ 67) showed a statistically significant difference in relapse-free survival and overall survival in favor of the HDAC6-positive group (Po0.02 and Po0.05, respectively). HDAC6 expression was an independent prognostic indicator by multivariate analysis (odds ratio ¼ 2.82, P ¼ 0.047). These results indicate the biological significance of HDAC6 regulation via estrogen signaling.