Amplified-in-breast cancer 1 (AIB1) is an overexpressed transcriptional coactivator in breast cancer. Although overproduced AIB1 is oncogenic, its role and underlying mechanisms in metastasis remain unclear. Here, mammary tumorigenesis and lung metastasis were investigated in wild-type (WT) and AIB1 ؊/؊ mice harboring the mouse mammary tumor virus-polyomavirus middle T (PyMT) transgene. All WT/PyMT mice developed massive lung metastasis, but AIB1 ؊/؊ /PyMT mice with comparable mammary tumors had significantly less lung metastasis. The recipient mice with transplanted AIB1 ؊/؊ /PyMT tumors also had much less lung metastasis than the recipient mice with transplanted WT/PyMT tumors. WT/PyMT tumor cells expressed mesenchymal markers such as vimentin and N-cadherin, migrated and invaded rapidly, and formed disorganized cellular masses in three-dimensional cultures. In contrast, AIB1؊/؊ /PyMT tumor cells maintained epithelial markers such as E-cadherin and ZO-1, migrated and invaded slowly, and still formed polarized acinar structures in three-dimensional cultures. Molecular analyses revealed that AIB1 served as a PEA3 coactivator and formed complexes with PEA3 on matrix metalloproteinase 2 (MMP2) and MMP9 promoters to enhance their expression in both mouse and human breast cancer cells. In 560 human breast tumors, AIB1 expression was found to be positively associated with PEA3, MMP2, and MMP9. These findings suggest a new alternative strategy for controlling the deleterious roles of these MMPs in breast cancer by inhibiting their upstream coregulator AIB1.The amplified-in-breast cancer 1 (AIB1) (also known as SRC-3, ACTR, and NCOA3) oncogene was initially identified in an amplified chromosomal 20q region in breast cancer cells (19) and subsequently characterized as a member of the p160 steroid receptor coactivator (SRC) family, which also contains SRC-1 and SRC-2 (TIF2 or GRIP1) (1,8,36,46,54). AIB1 interacts with nuclear hormone receptors such as estrogen and progesterone receptors and certain other transcription factors such as PEA3, E2F1, and AP-1 and serves as a transcriptional coactivator (18,30,32,54). In normal cells, AIB1 usually exists at limiting concentrations. Its coactivator activity is also modulated by posttranslational modifications including phosphorylation, ubiquitination, methylation, and isomerization (14, 52, 57). These modifications are regulated by steroid hormones, growth factors, and cytokines and are associated with cell cycle progression (30,52,53,59). The overexpression or overactivation of AIB1 in breast cancer cells enhances estrogen-induced cyclin D1 expression, epidermal growth factor receptor activation, cell proliferation, and antiestrogen resistance (27,28,38,59). The overexpression of AIB1 in prostate cancer cells increases Akt activation, cell size, and proliferation (61, 62). In addition, AIB1 deficiency dampens insulin-like growth factor I (IGF-I)-stimulated cell proliferation in mouse embryonic fibroblasts and mammary tumor cells (24,25,49). Therefore, AIB1 plays an important r...

Resting metabolic rate (RMR) was measured in 154 women and 48 men before the beginning of a weight reduction program. In both sexes there were significant univariate correlations between RMR and fat-free mass, body fat, weight, fat cell weight, and fat cell number (from total body water). Women also showed significant correlations between RMR and fat cell number (from total body potassium), free triiodothyronine index, and fasting and postglucose insulin levels. Multiple regression analysis showed that both fat-free mass and fat cell weight and number were significant predictors of RMR. The contribution of fat-free mass was three to five times greater per kg than that of body fat. There was no significant contribution of thyroid hormones or insulin to the prediction of RMR. Fat cell number and fat cell weight were significant predictors of RMR, whether determined from body water, body potassium, or a formula using both water and potassium. There was no significant difference in regression coefficients between men and women. Thus the difference in RMR between the sexes is probably caused by the higher proportion of fat-free mass in men. The effect of age was small and not statistically significant.

Background: The incidence of esophageal adenocarcinoma (EAC) is rapidly rising and has a 5-year survival rate of <20%. Beyond TNM (tumorenodeemetastasis) staging, no reliable risk stratification tools exist and no large-scale studies have profiled circulating tumor DNA (ctDNA) at relapse in EAC. Here we analyze the prognostic potential of ctDNA dynamics in EAC, taking into account clonal hematopoiesis with indeterminate potential (CHIP). Patients and methods: A total of 245 samples from 97 patients treated with neoadjuvant chemotherapy and surgery were identified from the prospective national UK Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) consortium data set. A pan-cancer ctDNA panel comprising 77 genes was used. Plasma and peripheral blood cell samples were sequenced to a mean depth of 7082Â (range 2196-28 524) and ctDNA results correlated with survival. Results: Characteristics of the 97 patients identified were as follows: 83/97 (86%) male, median age 68 years (SD 9.5 years), 100% cT3/T4, 75% cNþ. EAC-specific drivers had higher variant allele fractions than passenger mutations. Using stringent quality criteria 16/79 (20%) were ctDNA positive following resection; recurrence was observed in 12/16 (75%) of these. As much as 78/97 (80%) had CHIP analyses that enabled filtering for CHIP variants, which were found in 18/78 (23%) of cases. When CHIP was excluded, 10/63 (16%) patients were ctDNA positive and 9/10 of these (90%) recurred. With correction for CHIP, median cancer-specific survival for ctDNA-positive patients was 10.0 months versus 29.9 months for ctDNA-negative patients (hazard ratio 5.55, 95% confidence interval 2.42-12.71; P ¼ 0.0003). Similar outcomes were observed for disease-free survival. Conclusions: We demonstrate in a large, national, prospectively collected data set that ctDNA in plasma following surgery for EAC is prognostic for relapse. Inclusion of peripheral blood cell samples can reduce or eliminate false positives from CHIP. In future, post-operative ctDNA could be used to risk stratify patients into high-and low-risk groups for intensification or de-escalation of adjuvant chemotherapy.