No abstract

CHIP is a U-box-type ubiquitin ligase that induces ubiquitylation and degradation of its substrates, which include several oncogenic proteins. The relationship between CHIP and tumour progression, however, has not been elucidated. Here, we show that CHIP suppresses tumour progression in human breast cancer by inhibiting oncogenic pathways. CHIP levels were negatively correlated with the malignancy of human breast tumour tissues. In a nude mouse xenograft model, tumour growth and metastasis were significantly inhibited by CHIP expression. In contrast, knockdown of CHIP (shCHIP) in breast cancer cells resulted in rapid tumour growth and metastastic phenotypes in mice. In cell-based experiments, anchorage-independent growth and invasiveness of shCHIP cells was significantly elevated due to increased expression of Bcl2, Akt1, Smad and Twist. Proteomic analysis identified the transcriptional co-activator SRC-3 (refs 13, 14, 15, 16, 17, 18, 19) as a direct target for ubiquitylation and degradation by CHIP. Knocking down SRC-3 in shCHIP cells reduced the expression of Smad and Twist, and suppressed tumour metastasis in vivo. Conversely, SRC-3 co-expression prevented CHIP-induced suppression of metastasis formation. These observations demonstrate that CHIP inhibits anchorage-independent cell growth and metastatic potential by degrading oncogenic proteins including SRC-3.

Ipsilateral breast tumor relapse (IBTR) after breast-conserving treatment (BCT) may represent two distinct types of lesion, including a true recurrence (TR) or a new primary tumor (NPT). The aim of this study was to ascertain the difference between TRs and NPTs and to show the clinical significance of classifying IBTR into these two types of recurrence. Patients (n = 2,075) with unilateral invasive breast cancer who underwent BCT between 1987 and 2005 at Saitama Cancer Center were analyzed. IBTR was classified into TR and NPT, which was based on all clinical and pathological features of both a primary tumor and IBTR that can be evaluated. IBTR-free survival and the risk factors were analyzed in order to compare the findings for TR and NPT. In addition, the salvage surgical methods for IBTR and overall survival after IBTR were analyzed. Sixty patients with IBTR were classified into 52 with TR and eight with NPT. IBTR-free survival was significantly shorter in the patients with TR than those with NPT. Young age, tumor size, a positive surgical margin, and omission of radiation therapy (RT) were significant risk factors for TR. Omission of RT was the only significant risk factor for NPT. In 27 patients who underwent a repeat lumpectomy for TR, four had a second IBTR. The overall survival after IBTR was worse in patients with TR than NPT. TR and NPT show quite different clinical features. Classifying IBTR into TR or NPT can therefore help to select the most appropriate treatment for IBTR.

Extremely well-differentiated adenocarcinoma (EWDA) is an unusual gastric cancer that is histologically too bland to be diagnosed as malignant neoplasm, particularly using biopsy. EWDA may be a gastric counterpart of 'adenoma malignum' or minimal deviation adenocarcinoma (MDA) in the uterine cervix; however, the clinicopathological features of EWDA remain less apparent than those of MDA. A 60-year-old male was complaining of dysphagia. He had been made aware of a small submucosal tumor in the cardia 2 years before the onset of this symptom. Endoscopic ultrasonographic examination revealed a large cardiac tumor consisting of thickened layers, as observed in Borrmann type IV. Three mucosal biopsies suggested only benign changes including adenoma and hyperplastic polyps. At the fourth biopsy, cytologically bland columnar cells were located in the submucosa along with stromal fibrosis and laminated stones. The possibility that non-neoplastic aberrant pancreas with lithiasis formed the tumor was denied at laparotomy by a frozen section that revealed benign-looking glands invading the diaphragm. Immunohistochemically the cancer glands were positive for CA19-9 and human gastric mucin, but not for p53 or MUC2. To our knowledge, this is a previously unknown combination of EWDA and psammomatous calcification in the stomach.