Recent observations indicate that some sessile serrated adenomas (SSAs) have aberrant β-catenin nuclear labeling, implicating the Wnt pathway in the molecular progression of SSAs to colorectal carcinoma. We sought to expand upon this finding by characterizing β-catenin expression in the full spectrum of serrated colorectal polyps, and correlating these findings with the genetic status of BRAF, KRAS and CTNNB1. Immunolabeling for β-catenin confirmed the presence of abnormal nuclear accumulation in SSAs, with 35/54 (67%) SSAs showing nuclear labeling compared to 0/12 hyperplastic polyps (HPs). Abnormal nuclear labeling was also identified in 4/11 (36%) traditional serrated adenomas (TSAs) (p=0.00001). When SSAs were further analyzed with respect to the presence or absence of conventional epithelial dysplasia, nuclear β-catenin labeling was seen in 8/27 (29%) SSAs without dysplasia (SSA) but in 27/27 (100%) of SSAs with dysplasia (SSADs) (p=0.000001). Sequencing of genomic DNA extracted from a subset of HPs, SSAs, SSADs, TSAs and tubular adenomas (TAs) failed to identify any CTNNB1 mutations to account for abnormal β-catenin nuclear labeling. However, abnormal nuclear labeling always occurred in the setting of a BRAF V600E mutation, indicating aberrant nuclear labeling occurs on a background of BRAF activation. Of interest, all six TSAs contained a KRAS mutation confirming that SSAs and TSAs are genetically distinct entities. These findings validate previous reports implicating activation of the Wnt signaling pathway in SSAs, and further indicate that Wnt pathway activation plays a role in the neoplastic progression of SSAs and TSAs to colonic carcinoma by mechanisms independent of CTNNB1 mutation.

Previous studies have revealed that exogenous estrogen has a beneficial effect on the lipid profile; however, studies examining the relation between endogenous hormones and lipid profiles in postmenopausal women have yielded conflicting results. We sought to characterize the cross-sectional relationship between endogenous hormones and lipid parameters in postmenopausal women with significant (cases, n = 156) and minimal (controls, n = 172) carotid atherosclerosis not taking hormone therapy in the Atherosclerosis Risk in Communities Study. Endogenous hormone status was assessed by measuring levels of estrone, total testosterone, androstenedione, dehydroepiandrosterone sulfate, and SHBG. Free testosterone was estimated using the free androgen index (total testosterone/SHBG). Lipid parameters assessed included total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol. We found that SHBG was significantly associated with a more favorable lipid profile, including lower total and LDL cholesterol and triglycerides and higher HDL cholesterol among controls. This association was less prominent among cases where SHBG was only associated with higher triglycerides and lower HDL cholesterol. The free androgen index was associated with a more atherogenic lipid profile, including increased LDL cholesterol among controls and increased total and LDL cholesterol and triglycerides among cases. These relations were independent of demographic and metabolic factors and health behaviors. In contrast to controls, estrone was associated with higher total cholesterol and triglycerides among cases in multivariate analyses. Our data suggest that endogenous sex hormones may play a role in regulating lipid metabolism in postmenopausal women.

EphA2 is a transmembrane receptor tyrosine kinase that functions in the regulation of cell growth, survival, angiogenesis, and migration and EphA2 targeting has been proposed as a novel therapeutic strategy for neoplasms that overexpress this protein. EphA2 overexpression has been correlated with increased invasive and metastatic ability in pancreatic cancer cell lines. However, the patterns of EphA2 expression in human pancreatic cancers and associated metastases is unknown, as are the genetics of EphA2 in this tumor type. We collected clinicopathologic data and paraffin-embedded materials from 98 patients with primary and/or metastatic pancreatic cancer and performed immunohistochemical labeling for EphA2 protein. EphA2 protein immunolabeling was found in 207 of 219 samples (95%). The expression was predominantly cytoplasmic, although predominant membranous staining was observed in a minority of cases. When evaluated specifically for labeling intensity, primary and metastatic carcinomas were more strongly positive compared to benign ducts and PanIN lesions (P < 0.00001 and P < 0.01, respectively) and poorly differentiated carcinomas were more strongly positive for EphA2 than well and moderately differentiated tumors (P < 0.005). When primary carcinomas without metastatic disease were specifically compared to carcinomas with associated metastatic disease, the advanced carcinomas showed relatively less strong positive labeling for EphA2 (P < 0.008). Moreover, decreased EphA2 labeling was more commonly found in liver (P < 0.002), lung (P < 0.004) or peritoneal metastases (P < 0.01) as compared to distant lymph node metastases (P < 0.01). Genetic sequencing of the tyrosine kinase domain of EPHA2 in 22 samples of xenograft enriched pancreatic cancer did not reveal any inactivating mutations. However, EPHA2 amplification was found in 1 of 33 pancreatic cancers corresponding to a lymph node metastasis, indicating EPHA2 genomic amplification may underlie EphA2 overexpression in a minority of patients. Our data confirms that EphA2 is overexpressed in pancreatic cancer, but suggests a relative loss of EphA2 in co-existent pancreatic cancer metastases as well as a role for EPHA2 in organ specific metastasis.

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