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...

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The amplified in breast cancer-3 (AIB3, ASC-2, RAP250, PRIP, TRBP, NRC, or NcoA6) gene is characterized as a cancer-amplified transcriptional coactivator for nuclear receptors, which include the peroxisome proliferator-activated receptor ␥ (PPAR␥). To assess its biological function, we deleted the AIB3 gene in mice by homologous recombination. AIB3؉/؊ mice are developmentally normal and fertile. AIB3؊/؊ embryos exhibit growth restriction and lethality during 9.75-11.5 days postconception. The embryonic lethality is probably attributed to defects in the development of the placental vascular network and cardiac hypoplasia. These defects include the failure of labyrinthine development, the dilation of maternal blood sinuses, the massive erythrophagocytosis by trophoblasts, the alteration of trophoblast populations, and the lower proliferation of myocardium, which are similar to those encountered in mice lacking PPAR␥ or the PPAR␥-binding protein (PBP, TRAP220, or DRIP205). In addition, the transcriptional activities of PPAR␥ are significantly affected in mouse embryonic fibroblasts lacking AIB3. These results suggest that AIB3 is required for PPAR␥ function in placental development and for normal heart development. These results also indicate that the biological function of AIB3 is not redundant with other classes of nuclear receptor coactivators such as PBP and members of the steroid receptor coactivator family.

Hypoxia-induced inflammation and excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) play important roles in the pathological process of hypoxic pulmonary hypertension (HPH). Melatonin possesses anti-inflammatory and antiproliferative properties. However, the effect of melatonin on HPH remains unclear. In this study, adult Sprague-Dawley rats were exposed to intermittent chronic hypoxia for 4 wk to mimic a severe HPH condition. Hemodynamic and pulmonary pathomorphology data showed that chronic hypoxia significantly increased right ventricular systolic pressures (RVSP), weight of the right ventricle/left ventricle plus septum (RV/LV+S) ratio, and median width of pulmonary arterioles. Melatonin attenuated the elevation of RVSP, RV/LV+S, and mitigated the pulmonary vascular structure remodeling. Melatonin also suppressed the hypoxia-induced high expression of proliferating cell nuclear antigen (PCNA), hypoxia-inducible factor-1α (HIF-1α), and nuclear factor-κB (NF-κB). In vitro, melatonin concentration-dependently inhibited the proliferation of PASMCs and the levels of phosphorylation of Akt and extracellular signal-regulated kinases1/2 (ERK1/2) caused by hypoxia. These results suggested that melatonin might potentially prevent HPH via anti-inflammatory and antiproliferative mechanisms.