The EGFR/PI3K/PTEN/Akt/mTORC1/GSK-3 pathway plays prominent roles in malignant transformation, prevention of apoptosis, drug resistance and metastasis. The expression of this pathway is frequently altered in breast cancer due to mutations at or aberrant expression of: HER2, ERalpha, BRCA1, BRCA2, EGFR1, PIK3CA, PTEN, TP53, RB as well as other oncogenes and tumor suppressor genes. In some breast cancer cases, mutations at certain components of this pathway (e.g., PIK3CA) are associated with a better prognosis than breast cancers lacking these mutations. The expression of this pathway and upstream HER2 has been associated with breast cancer initiating cells (CICs) and in some cases resistance to treatment. The anti-diabetes drug metformin can suppress the growth of breast CICs and herceptin-resistant HER2+ cells. This review will discuss the importance of the EGFR/PI3K/PTEN/Akt/mTORC1/GSK-3 pathway primarily in breast cancer but will also include relevant examples from other cancer types. The targeting of this pathway will be discussed as well as clinical trials with novel small molecule inhibitors. The targeting of the hormone receptor, HER2 and EGFR1 in breast cancer will be reviewed in association with suppression of the EGFR/PI3K/PTEN/Akt/mTORC1/GSK-3 pathway.

Merkel cell carcinoma is a cutaneous neuroendocrine neoplasm that has been poorly studied in contemporary cohorts. Patients with Merkel cell carcinoma from 1986 to 2011 were identified in the Surveillance Epidemiology and End Results registry. A total of 5211 patients met the inclusion criteria. The mean age was 74.9 years; majority were male (61.4%) and white (94.9%). Patients were divided into two cohorts: Group 1 (1986 and 1999) and Group 2 (1999–2010). Group 2 was more likely to have Stage III disease (14.6 vs 23.3%, P < 0.001) and less likely to have Stage I/II disease (71.8 vs 65.1%, P < 0.0001). The increase in Stage III was likely secondary to increased use of sentinel lymph node biopsy. Disease-specific five-year survival for Stages I/II was 78.1 per cent and Stage III was 54 per cent. Disease-specific five-year survival was unchanged between Groups 1 and 2, 69.9 versus 66.6 per cent, respectively ( P = 0.44). Both incidence and mortality significantly increased over the study period with P value for both trends <0.0001. In 1986, incidence and mortality rates per 100,000 were 0.22 and 0.03, respectively, and increased to 0.79 and 0.43 in 2011, respectively. There has been a greater than 333 per cent increase in mortality from Merkel cell carcinoma.

Cutaneous apocrine adenocarcinoma is a rare neoplasm. Excision is standard treatment. The most important predictor of survival in localized disease is lymph node status; therefore, sentinel lymph node biopsy could be considered in management of this disease.

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that participates in an array of critical cellular processes. GSK-3 was first characterized as an enzyme that phosphorylated and inactivated glycogen synthase. However, subsequent studies have revealed that this moon-lighting protein is involved in numerous signaling pathways that regulate not only metabolism but also have roles in: apoptosis, cell cycle progression, cell renewal, differentiation, embryogenesis, migration, regulation of gene transcription, stem cell biology and survival. In this review, we will discuss the roles that GSK-3 plays in various diseases as well as how this pivotal kinase interacts with multiple signaling pathways such as: PI3K/PTEN/Akt/mTOR, Ras/Raf/MEK/ERK, Wnt/beta-catenin, hedgehog, Notch and TP53. Mutations that occur in these and other pathways can alter the effects that natural GSK-3 activity has on regulating these signaling circuits that can lead to cancer as well as other diseases. The novel roles that microRNAs play in regulation of the effects of GSK-3 will also be evaluated. Targeting GSK-3 and these other pathways may improve therapy and overcome therapeutic resistance.

Colorectal cancer (CRC) is the third leading cause of cancer death in the United States, resulting in an average of 50,000 deaths per year. Surgery and combination chemotherapy comprise current treatment strategies. However, curative options are limited if surgery and chemotherapy are unsuccessful. Several studies have indicated that CRC aggressiveness and potential for metastatic spread are associated with the acquisition of stem cell like properties. The Notch-1 receptor and its cognate signaling pathway is well known for controlling cell fate decisions and stem-cell phenotypes. Alterations in Notch receptors and Notch signaling has been reported for some colon cancers. Herein, we examine a potential role for Notch-1 signaling in CRC. In CRC patient samples, Notch-1 expression was increased in colon tumor tissue as compared with normal colon tissue. Retroviral transduction of constitutively active Notch-1 (ICN1) into the colon tumor cell line HCT-116 resulted in increased expression of the EMT/stemness associated proteins CD44, Slug, Smad-3, and induction of Jagged-1 expression. These changes in ICN1 expressing cells were accompanied by increased migration and increased anchorage independent growth by 2.5-fold and 23%, respectively. Experiments with the pan-Notch inhibitor DAPT, and soluble Jagged-1-Fc protein provided evidence that Notch-1 signaling activates CD44, Slug, and Smad-3 via a cascade of other Notch-receptors through induction of Jagged-1 expression. These data indicate a key role for Notch signaling in the phenotype of CRC and suggest that targeting of Notch signaling may be of therapeutic value in colon cancers.

Objective To examine the disability, health care resource utilization, and direct annual costs among patients with migraine, categorized according to the number of headache days experienced in the past month. Background Migraine exists on a continuum of different attack frequencies and associated levels of disability. People with migraine have increased health care utilization and incur substantially more direct costs than those without the disease. While the broad implications of migraine are evident, there is a need to comprehensively describe the impact of headache frequency on the burden of illness. Design/Methods Data from a cross‐sectional, self‐administered, Internet‐based survey of respondents recruited from the US National Health and Wellness Survey panel were assessed. Adults who had self‐reported migraine diagnosis or migraine symptoms in the past 3 months were grouped by their frequency of headache days in the past month: low‐frequency episodic migraine (LFEM, <4 days), moderate‐frequency episodic migraine (MFEM, 4–9 days), high‐frequency episodic migraine (HFEM, 10–14 days), and chronic migraine (CM, ≥15 days). Headache‐related disability was determined from the Headache Impact Test (HIT‐6) scores, and health care resource utilization was assessed by the number of ER visits, hospitalizations, and visits to health care practitioners (HCPs) in the past 12 months. The estimated annual direct costs were calculated from the number of each type of visit and all‐cause cost data from the 2014 Medical Expenditure Panel Survey. Results A total of 1347 patients (LFEM, n = 813; MFEM, n = 301; HFEM, n = 105; CM, n = 128) were included. Patient groups differed significantly by comorbidity index, education and income level, alcohol consumption, and insurance type. Overall, patients with LFEM had the least disability and lowest health care utilization and direct costs. Patients with CM scored 3.7 points (adjusted mean score [95% confidence interval, CI] 68.2 [67.3, 69.0] points) higher on HIT‐6 compared with those in the LFEM group (64.5 points [64.1, 64.8]), while those with HFEM and MFEM scored 2.4 (66.8 points [65.9, 67.8]) and 2.3 (66.7 points [66.2, 67.3]) points higher, respectively (all, P < .001). The CM and MFEM groups reported significantly more HCP visits ([mean ± standard error] CM: 7.03 ± 0.83; MFEM: 5.34 ± 0.42; vs LFEM: 3.48 ± 0.18; both, P < .001) and migraine‐related hospitalizations (CM: 0.06 ± 0.03; MFEM: 0.05 ± 0.02; vs LFEM: 0.02 ± 0.01; both, P < .05) than the LFEM group. There were significant differences in the total direct costs between the CM and MFEM groups compared with the LFEM group (CM: $3155 ± $609; MFEM: $2721 ± $342; vs LFEM: $1560 ± $118; both, P < .001), with differences largely driven by costs of HCP visits. Conclusions In patients with migraine, as the number of headache days increased, so did the burden of disease (disability, health care utilization, and direct costs). Elucidating the burden associated with EM and CM has implications for guiding treatment decisions and managem...

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Various signaling pathways exert critical roles in the epithelial to mesenchymal transition (EMT) and cancer stem cells (CSCs). The Wnt/beta-catenin, PI3K/PTEN/Akt/mTORC, Ras/Raf/MEK/ERK, hedgehog (Hh), Notch and TP53 pathways elicit essential regulatory influences on cancer initiation, EMT and progression. A common kinase involved in all these pathways is moon-lighting kinase glycogen synthase kinase-3 (GSK-3). These pathways are also regulated by micro-RNAs (miRs). TP53 and components of these pathways can regulate the expression of miRs. Targeting members of these pathways may improve cancer therapy in those malignancies that display their abnormal regulation. This review will discuss the interactions of the multi-functional GSK-3 enzyme in the Wnt/beta-catenin, PI3K/PTEN/Akt/mTORC, Ras/Raf/MEK/ERK, Hh, Notch and TP53 pathways. The regulation of these pathways by miRs and their effects on CSC generation, EMT, invasion and metastasis will be discussed.