MTA1 Interacts with MAT1, a cyclin-dependent kinase-activating kinase complex ring finger factor and regulates estrogen receptor transactivation functions

The transcriptional activity of estrogen receptor-α is controlled by coregulators. MTA1 (metastasis-associated protein1) represses estrogen receptor-α-driven transcription by recruiting Histone Deacetylases (HDACs) to the estrogen response element containing target gene chromatin in breast cancer cells. Using a yeast two-hybrid screen with the MTA1 C-terminal domain as bait, we identified MAT1 (menage a trois 1) as an MTA1-binding protein. MAT1 is an assembly/targeting factor for cyclin-dependent kinase-activating kinase (CAK), which has been shown to functionally interact with general transcriptional factor TFIIH, a known inducer of ER transactivation. We show that estrogen signaling promotes nuclear translocation of MAT1 and that MTA1 interacts with MAT1 both in vitro and in vivo. MAT1 binds to the C-terminal 389–441 amino acids GATA domain and N-terminal 1–164 amino acids bromo-domain of MTA1, whereas MTA1 binds to the N-terminal ring finger domain of the MAT1. In addition, MAT1 interacts with the activation function 2 domain of ER and colocalizes with ER in activated cells. MTA1 deregulation in breast cancer cells led to its interactions with the CAK complex components, ER and HDAC2. Accordingly, MTA1 inhibited CAK stimulation of ER transactivation that was partially relieved by HDAC inhibitor trichostatin A, suggesting that MTA1 might inhibit CAK-induced transactivation function of ER by recruiting HDAC. Furthermore, MTA1 overexpression inhibited the ability of CAK complex to phosphorylate ER. Together, these findings identified MAT1 as a target of MTA1 and provided new evidence to suggest that the transactivation functions of ER might be influenced by the regulatory interactions between CAK and MTA1 in breast cancer cells

DEAR1 Is a Dominant Regulator of Acinar Morphogenesis and an Independent Predictor of Local Recurrence-Free Survival in Early-Onset Breast Cancer

Ann Killary and colleagues describe a new gene that is genetically altered in breast tumors, and that may provide a new breast cancer prognostic marker

Definitive characterization of CA 19-9 in resectable pancreatic cancer using a reference set of serum and plasma specimens

The validation of candidate biomarkers often is hampered by the lack of a reliable means of assessing and comparing performance. We present here a reference set of serum and plasma samples to facilitate the validation of biomarkers for resectable pancreatic cancer. The reference set includes a large cohort of stage I-II pancreatic cancer patients, recruited from 5 different institutions, and relevant control groups. We characterized the performance of the current best serological biomarker for pancreatic cancer, CA 19-9, using plasma samples from the reference set to provide a benchmark for future biomarker studies and to further our knowledge of CA 19-9 in early-stage pancreatic cancer and the control groups. CA 19-9 distinguished pancreatic cancers from the healthy and chronic pancreatitis groups with an average sensitivity and specificity of 70-74%, similar to previous studies using all stages of pancreatic cancer. Chronic pancreatitis patients did not show CA 19-9 elevations, but patients with benign biliary obstruction had elevations nearly as high as the cancer patients. We gained additional information about the biomarker by comparing two distinct assays. The two CA 9-9 assays agreed well in overall performance but diverged in measurements of individual samples, potentially due to subtle differences in antibody specificity as revealed by glycan array analysis. Thus, the reference set promises be a valuable resource for biomarker validation and comparison, and the CA 19-9 data presented here will be useful for benchmarking and for exploring relationships to CA 19-9

Metastasis-associated protein 1 short form stimulates Wnt1 pathway in mammary epithelial and cancer cells

Although Wnt1 downstream signaling components as well as cytoplasmic level of metastatic tumor antigen 1 short-form (MTA1s) have been shown to be elevated in human breast cancer, it remains unknown whether a regulatory cross-talk exists between these two pathways. Here we provide evidence of a remarkable correlation between the levels of MTA1s and stimulation of the Wnt1 signaling components, leading to increased stabilization of β-catenin, and stimulation of Wnt1 target genes in the murine mammary epithelial and human breast cancer cells. We found that MTA1s influences Wnt1 pathway via ERK signaling as selective silencing of the endogenous MTA1s or ERK or its target GSK-3β resulted in a substantial decrease in β-catenin expression, leading to inhibition of Wnt1-target genes. Furthermore, downregulation of β-catenin in cells with elevated MTA1s level was accompanied by a corresponding decrease in the expression of Wnt1 target genes, establishing a mechanistic role for the ERK/GSK-3β/ β-catenin pathway in the stimulation of the Wnt1 target genes by MTA1s in mammary epithelial cells. In addition, mammary glands from the virgin MTA1s transgenic mice mimicked the phenotypic changes found in the Wnt1 transgenic mice and exhibited an overall hyperactivation of the Wnt1 signaling pathway, leading to increased stabilization and nuclear accumulation of β-catenin. Mammary glands from the virgin MTA1s-TG mice revealed ductal hyperplasia and ductal carcinoma in situ, and low incidence of palpable tumors. These findings reveal a previously unrecognized role for MTA1s as an important modifier of the Wnt1 signaling in mammary epithelial and cancer cells

Functional regulation of oestrogen receptor pathway by the dynein light chain 1

Overexpression and phosphorylation of dynein light chain 1 (DLC1) have been shown to promote the growth of breast cancer cells. However, the role of DLC1 in the action of the oestrogen receptor (ER) remains unknown. Here, we found that oestrogen induces the transcription and expression of DLC1. DLC1 facilitated oestrogen-induced ER transactivation and anchorage-independent growth of breast cancer cells. We show that DLC1 interacts with ER, and such interaction is required for the transactivation-promoting activity of DLC1. Further, DLC1 expression led to enhanced recruitment of the DLC1–ER complex to the ER-target gene chromatin. Conversely, DLC1 downregulation compromised the ER-transactivation activity and also its nuclear accumulation, suggesting a potential chaperone-like activity of DLC1 in the nuclear translocation of ER. Together, these data define an unexpected upregulation of DLC1 by oestrogen and a previously unrecognized DLC1–ER interaction in supporting and amplifying ER-initiated cellular responses in breast cancer cells