Emerging evidence supports neurotensin as a trophic and antiapoptotic factor, mediating its control via the highaffinity neurotensin receptor (NT1 receptor) in several human solid tumors. In a series of 51 patients with invasive ductal breast cancers, 34% of all tumors were positive for neurotensin and 91% positive for NT1 receptor. We found a coexpression of neurotensin and NT1 receptor in a large proportion (30%) of ductal breast tumors, suggesting a contribution of the neurotensinergic signaling cascade within breast cancer progression. Functionally expressed NT1 receptor, in the highly malignant MDA-MB-231 human breast cancer cell line, coordinated a series of transforming functions, including cellular migration, invasion, induction of the matrix metalloproteinase (MMP)-9 transcripts, and MMP-9 gelatinase activity. Disruption of NT1 receptor signaling by silencing RNA or use of a specific NT1 receptor antagonist, SR48692, caused the reversion of these transforming functions and tumor growth of MDA-MB-231 cells xenografted in nude mice. Our findings support the contribution of neurotensin in human breast cancer progression and point out the utility to develop therapeutic molecules targeting neurotensin or NT1 receptor signaling cascade. These strategies would increase the range of therapeutic approaches and be beneficial for specific patients. (Cancer Res 2006; 66(12): 6243-9)

BackgroundThe neurotensin (NTS) and its specific high affinity G protein coupled receptor, the NT1 receptor (NTSR1), are considered to be a good candidate for one of the factors implicated in neoplastic progression. In breast cancer cells, functionally expressed NT1 receptor coordinates a series of transforming functions including cellular migration and invasion.Methods and Resultswe investigated the expression of NTS and NTSR1 in normal human breast tissue and in invasive ductal breast carcinomas (IDCs) by immunohistochemistry and RT-PCR. NTS is expressed and up-regulated by estrogen in normal epithelial breast cells. NTS is also found expressed in the ductal and invasive components of IDCs. The high expression of NTSR1 is associated with the SBR grade, the size of the tumor, and the number of metastatic lymph nodes. Furthermore, the NTSR1 high expression is an independent factor of prognosis associated with the death of patients.Conclusionthese data support the activation of neurotensinergic deleterious pathways in breast cancer progression.

Alterations in the Wnt/APC (adenomatous polyposis coli) signalling pathway, resulting in beta-catenin/T cell factor (Tcf)-dependent transcriptional gene activation, are frequently detected in familial and sporadic colon cancers. The neuropeptide neurotensin (NT) is widely distributed in the gastrointestinal tract. Its proliferative and survival effects are mediated by a G-protein coupled receptor, the NT1 receptor. NT1 receptor is not expressed in normal colon epithelial cells, but is over expressed in a number of cancer cells and tissues suggesting a link to the outgrowth of human colon cancer. Our results demonstrate that the upregulation of NT1 receptor occurring in colon cancer is the result of Wnt/APC signalling pathway activation. We first established the functionality of the Tcf response element within the NT1 receptor promoter. Consequently, we observed the activation of NT1 receptor gene by agents causing beta-catenin cytosolic accumulation, as well as a strong decline of endogenous receptor when wt-APC was restored. At the cellular level, the re-establishment of wt-APC phenotype resulted in the impaired functionality of NT1 receptor, like the breakdown in NT-induced intracellular calcium mobilization and the loss of NT pro-invasive effect. We corroborated the Wnt/APC signalling pathway on the NT1 receptor promoter activation with human colon carcinogenesis, and showed that NT1 receptor gene activation was perfectly correlated with nuclear or cytoplasmic beta-catenin localization while NT1 receptor was absent when beta-catenin was localized at the cell-cell junction in early adenomas of patients with familial adenomatous polyposis, hereditary non-polyposis colorectal cancer and loss of heterozygosity tumours. In this report we establish a novel link in vitro between the Tcf/beta-catenin pathway and NT1 receptor promoter activation.

Endometriosis is a common inflammatory gynecological disorder which causes pelvic scarring, pain, and infertility, characterized by the implantation of endometrial-like lesions outside the uterus. The peritoneum, ovaries, and deep soft tissues are the commonly involved sites, and endometriotic lesions can be classified into three subphenotypes: superficial peritoneal endometriosis (PE), ovarian endometrioma (OE), and deep infiltrating endometriosis (DIE). In 132 women diagnosed laparoscopically with and without endometriosis (n = 73, 59 respectively), and stratified into PE, OE, and DIE, peritoneal fluids (PF) were characterized for 48 cytokines by using multiplex immunoassays. Partial-least-squares-regression analysis revealed distinct subphenotype cytokine signatures—a six-cytokine signature distinguishing PE from OE, a seven-cytokine signature distinguishing OE from DIE, and a six-cytokine-signature distinguishing PE from DIE—each associated with different patterns of biological processes, signaling events, and immunology. These signatures describe endometriosis better than disease stages (p < 0.0001). Pathway analysis revealed the association of ERK1 and 2, AKT, MAPK, and STAT4 linked to angiogenesis, cell proliferation, migration, and inflammation in the subphenotypes. These data shed new insights on the pathophysiology of endometriosis subphenotypes, with the potential to exploit the cytokine signatures to stratify endometriosis patients for targeted therapies and biomarker discovery.

A case is reported of early onset ovarian hyperstimulation syndrome (OHSS) after gonadotrophin-releasing hormone agonist (GnRHa) trigger for final oocyte maturation in a GnRH antagonist protocol. The use of GnRHa in place of HCG as a trigger for final oocyte maturation in an antagonist IVF cycle has been proposed as a method for preventing OHSS in predicted high-responders. This approach, however, did not prevent the occurrence of OHSS in our case despite a freeze-all strategy. To the best of our knowledge, this is a possible index case of severe OHSS with GnRHa trigger for oocyte maturation without any luteal HCG rescue for a high responder, despite IVF cycle segmentation.

BackgroundAntral follicle count (AFC) and anti-Mullerian hormone (AMH) are known as the most reliable markers of a woman’s ovarian reserve and are related to age. There is currently no specific local age-related centile charts for AFC and AMH. Therefore, we aim to examine the relationship between AFC and AMH with age and construct age-related nomograms among a subfertile Asian population.MethodsThis is a study involving Chinese women who had their AFC and AMH measured as part of their subfertility screening from December 2010 until November 2014 in KK Women’s and Children’s Hospital, Singapore. Ordinary least squares regression analysis was used to estimate the relationship of AFC and AMH with age, while age-related AFC and AMH nomograms for the 3rd, 10th, 25th, 50th, 75th, 90th and 97th percentiles were produced using the lambda-mu-sigma method.ResultsA total of 1,009 women, aged 26 to 44 year-old, were included. On average, the AFC and AMH decreased respectively by 0.79 follicle (95% confidence interval -0.93, -0.64) and 0.38 ng/mL (95% confidence interval -0.43, -0.32) per year of age. The age-related nomograms of AFC showed an approximately linear pattern, inversely correlated with age, regardless of the percentile. For AMH, the pattern is linear for the 75th percentile and below but shows a slightly accelerating decline for the 90th and 97th percentile. Overall, there were large inter-individual variations in AFC and AMH up to about 40 year-old.ConclusionThe declines of AFC and AMH over age are mostly linear among subfertile Chinese women in Singapore. The age-related AFC and AMH nomograms could be used as a reference chart by fertility practitioners. However, future validation with longitudinal data is required.

Our data recommend the simplified PCOS criteria with population-specific thresholds for diagnosis of PCOS. Its ability to replace ovarian ultrasound biometry with the highly correlated variable AMH, and use of testosterone as a single marker for hyperandrogenaemia alongside the key symptoms of oligomenorrhoea and hirsutism confers significant clinical potential for the diagnosis of PCOS.

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