The Role of Notch Signaling and Leptin-Notch Crosstalk in Pancreatic Cancer.

There is accumulating evidence that deregulated Notch signaling affects cancer development, and specifically pancreatic cancer (PC) progression. Notch canonical and non-canonical signaling has diverse impact on PC. Moreover, the actions of RBP-Jk (nuclear partner of activated Notch) independent of Notch signaling pathway seem to affect differently cancer progression. Recent data show that in PC and other cancer types the adipokine leptin can modulate Notch/RBP-Jk signaling, thereby, linking the pandemic obesity with cancer and chemoresistance. The potential pivotal role of leptin on PC, and its connection with Notch signaling and chemoresistance are still not completely understood. In this review, we will describe the most important aspects of Notch-RBP-Jk signaling in PC. Further, we will discuss on studies related to RBP-Jk-independent Notch and Notch-independent RPB-Jk signaling. We will also discuss on the novel crosstalk between leptin and Notch in PC and its implications in chemoresistance. The effects of leptin-Notch/RBP-Jk signaling on cancer cell proliferation, apoptosis, and drug resistance require more investigation. Data from these investigations could help to open unexplored ways to improve PC treatment success that has shown little progress for many years.

New Developments in Breast Cancer and Their Impact on Daily Practice in Pathology.

Advances in research have transformed our understanding of breast cancers and have altered the daily practice of pathology. Theranostic evaluations performed by pathologists are now critical in triaging the patients into appropriate treatment groups, as are new guidelines that were recently established for the evaluation of HER2/neu gene amplification. Emerging molecular classifications of breast cancers bring novel perspectives to the assessment of individual cases, and opportunities for better treatments. Molecular studies have particularly shed light on distinct biological subsets of triple-negative breast cancers, for which new targeted therapies are being developed. The prognostic and therapeutic utility of new histopathologic parameters, such as tumor-infiltrating lymphocytes, are also being elucidated, and new protocols have been devised for the pathologic evaluation of breast specimens that have undergone neoadjuvant treatment. Novel clinical practices, such as radioactive seed localization, also affect the way breast specimens are processed and evaluated. In this brief review, we highlight the developments that are most relevant to pathology and are changing or could potentially impact our daily practice.

Molecular cues on obesity signals, tumor markers and endometrial cancer.

Tumor markers are important tools for early diagnosis, prognosis, therapy response and endometrial cancer monitoring. A large number of molecular and pathologic markers have been described in types I and II endometrial cancers, which has served to define the main oncogenic, epidemiological, genetic, clinical and histopathological features. Ongoing attempts to stratify biological markers of endometrial cancer are presented. However, data on changes in tumor marker profiles in obesity-related endometrial cancer are scarce. Obesity is a pandemic in Western countries that has an important impact on endometrial cancers, albeit through not very well-defined mechanisms. Although endometrial cancer is more common in Caucasian women, higher mortality is found in African Americans who also show higher incidence of obesity. Here, we describe how obesity signals (estrogen, leptin, leptin induced-molecules, Notch; cytokines and growth factors) could affect endometrial cancer. Leptin signaling and its crosstalk may be associated to the more aggressive and poor prognosis type II endometrial cancer, which affects more postmenopausal and African-American women. In this regard, studies on expression of novel molecular markers (Notch, interleukin-1 and leptin crosstalk outcome) may provide essential clues for detection, prevention, treatment and prognosis.

IRAK4 and TLR3 Sequence Variants may Alter Breast Cancer Risk among African-American Women.

Mounting evidence suggests that imbalances in immune regulation contribute to cell transformation. Women of African descent are an understudied group at high risk for developing aggressive breast cancer (BrCa). Therefore, we examined the role of 16 innate immune single nucleotide polymorphisms (SNPs) in relation to BrCa susceptibility among 174 African-American women in Atlanta, GA, USA. SNPs were examined in germ-line DNA collected from 102 BrCa patients and 72 women with benign nodules using SNPstream methodology. Inheritance of the TLR3 rs10025405 GG genotype was associated with an 82% decrease in BrCa risk. In contrast, individuals who possessed at least one IRAK4 rs4251545 T allele had a 1.68- to 4.99-fold increase in the risk of developing BrCa relative to those with the referent genotype (OR = 4.99; 95% CI = 1.00, 25.00; p = 0.0605). However, the IRAK4 rs4251545 locus was only significant under the additive genetic model (p trend = 0.0406). In silico predictions suggest IRAK4 rs4251545 SNP falls within a transcription enhancer/silencer region of the gene and codes for an Ala428Thr amino acid change. This missense mutation introduces a potential phosphorylation site in the extreme carboxy terminus (XCT) of the IRAK4 kinase domain. Preliminary molecular modeling predicts that this SNP stabilizes two alpha helices within the XCT on the surface of the IRAK4 kinase domain and increases the size of the groove between them. Our in silico results, combined with previous reports noting the presence of IRAK4 and XCT fragments in mouse and human serum, suggest the possibility that the XCT subdomain of IRAK4 possesses biological function. These findings require further evaluation and validation in larger populations, additional molecular modeling as well as functional studies to explore the role of IRAK4 and its XCT in cell transformation and innate immunity.

Survivin upregulation, dependent on leptin-EGFR-Notch1 axis, is essential for leptin-induced migration of breast carcinoma cells.

Obese breast cancer patients exhibit a higher risk for larger tumor burden and an increased likelyhood of metastasis. The molecular effects of obesity on carcinogenesis are mediated by the autocrine and paracrine effects of the adipocytokine leptin. Leptin participates in the tumor progression and metastasis of human breast. We show that leptin induces clonogenicity and increases the migration potential of breast cancer cells. We found that survivin expression is induced in response to leptin. In this study, we examine the role and leptin-mediated regulation of survivin. Leptin treatment leads to survivin upregulation, due in part to the activation of Notch1 and the release of a transcriptionally active Notch1 intracellular domain (NICD). Chromatin immunoprecipitation analysis shows that NICD gets recruited to the survivin promoter at the CSL (CBF1/RBP-Jk, Su(H), Lag-1) binding site in response to leptin treatment. Inhibition of Notch1 activity inhibits leptin-induced survivin upregulation. Leptin-induced transactivation of epidermal growth factor receptor (EGFR) is involved in leptin-mediated Notch1 and survivin upregulation, demonstrating a novel upstream role of leptin-EGFR-Notch1 axis. We further show that leptin-induced migration of breast cancer cells requires survivin, as overexpression of survivin further increases, whereas silencing survivin abrogates leptin-induced migration. Using a pharmacological approach to inhibit survivin, we show that 3-hydroxy-3-methylglutaryl-coenzyme-A-reductase inhibitors, such as lovastatin, can effectively inhibit leptin-induced survivin expression and migration. Importantly, leptin increased breast tumor growth in nude mice. These data show a novel role for survivin in leptin-induced migration and put forth pharmacological survivin inhibition as a potential novel therapeutic strategy. This conclusion is supported by in vivo data showing the overexpression of leptin and survivin in epithelial cells of high-grade ductal carcinomas in situ and in high-grade invasive carcinomas.

High prevalence of triple-negative tumors in an urban cancer center.

BACKGROUND: A disparate proportion of breast cancer deaths occur among young women, those of African-American (AA) ancestry, and particularly young AA women. Estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor-2 (HER-2) are key clinically informative biomarkers. The triple-negative (ER-/PR-/HER-2-) tumor subgroup is intrinsically resistant to treatment and portends a poor prognosis. Age, race, and socioeconomic status have been associated with triple-negative tumors (TNT). In the current study, the authors investigated breast cancer subgroups among patients in an urban cancer center serving a multiracial, low socioeconomic population. METHODS: This case series analyzed female invasive breast cancers diagnosed and/or treated between 2003 and 2004 in the AVON Comprehensive Breast Center at Grady Hospital in Atlanta, Georgia. Data were obtained from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program, and augmented by the hospital registry and pathology reports. Statistical analyses utilized frequency distributions and logistic regression. RESULTS: Of 190 breast cancers; 167 (88%) were diagnosed among AA and 23 (12%) were diagnosed among non-AA women. The median age at diagnosis in the 2 groups was 58 years and 57 years, respectively. TNT prevalence was found to differ by race (29.3% among AA women and 13.0% among non-AA women; P = .010). Differences persisted after adjustment for age and stage (odds ratio [OR] of 3.1; 95%confidence interval [95% CI], 0.8-11.6). The majority of recurrences (40.0%) occurred among women with TNT, who were also most likely to experience a fatal event (OR of 3.7; 95%CI, 1.1-13.0). CONCLUSIONS: Despite a similarity in their age at diagnosis, AA women in our urban cancer center presented with a higher prevalence of TNT and TNT was found to predict the poorest outcomes. Institutional interactive breast conferences and intervention/navigation programs could help to dispel breast cancer disparities and improve outcomes.