Circulating and/or cutaneous irisin resistance: A novel link among androgenetic alopecia, comorbid metabolic syndrome and cardiovascular risks.

BACKGROUND: Androgenetic alopecia (AGA) is a common cause of hair loss in both genders that may be associated with disturbed systemic metabolism. Irisin is a hormone-like myokine that greatly influences systemic metabolism and is linked to cardiovascular diseases. AIM: To detect irisin role in AGA and its associated metabolic syndrome (MetS) and cardiovascular risk. PATIENTS/METHODS: This case-control study included 44 AGA patients of both genders and 22 healthy individuals. Serum irisin level was measured using ELISA and scalp biopsy was taken to detect irisin immunohistochemically. Carotid Doppler ultrasonography was performed to measure carotid intima media thickness (CIMT). RESULTS: Higher serum irisin was significantly detected in AGA patients (p ˂ 0.001), and in males (p = 0.01) particularly severe cases (p ˂ 0.001). It was significantly higher in AGA patients presenting with MetS and those suffering from dyslipidemia (p ˂ 0.001 for both). Multivariate regression analysis proved BMI (p = 0.01) and serum irisin (p = 0.02) as independent predictors of CIMT abnormality among AGA patients. Regarding cutaneous irisin expression, the epidermal H-score was significantly higher in AGA patients with MetS compared to those without (p = 0.04). Epidermal H-score ˃100 was significantly associated with male gender (p = 0.05), severe AGA (p = 0.02), MetS (p = 0.03), dyslipidemia (p = 0.03), and abnormal CIMT (p = 0.03). CONCLUSION: High serum irisin and upregulated epidermal irisin expression are associated with the incidence of MetS, dyslipidemia, and CIMT abnormality among AGA patients. This may indicate resistance to irisin, which hinders its favorable cardiometabolic actions. Further studies are warranted to investigate the concept of irisin resistance in AGA patients, which was uniquely discussed in the present study.

Expression Profile of Myoepithelial Cells in DCIS: Do They Change From Protective Angels to Wicked Witches?

The mechanism of transition of ductal carcinoma in situ (DCIS) to invasive cancer is elusive but recently changes in the myoepithelial cells (MECs) have been implicated. The aim of this study is to investigate the changes in gene profile of MECs in DCIS that could compromise their tumor suppressor function leading to promotion of tumor progression. Immuno-laser capture microdissection (LCM) was used to isolate MECs from normal and DCIS breast tissues followed by whole genome expression profiling using Affymetrix HGU-133 plus2.0 arrays. The data were analyzed using Bioconductor packages then validated by using real-time quantitative polymerase chain reaction and immunohistochemistry. Ingenuity Pathways software analysis showed clustering of most of the altered genes in cancer and cell death networks, with the Wnt/B-catenin pathway as the top canonical pathway. Validation revealed a 71.4% correlation rate with the array results. Most dramatic was upregulation of Fibronectin 1 ( FN1 ) in DCIS-associated MECs. Immunohistochemistry analysis for FN1 on normal and DCIS tissues confirmed a strong correlation between FN1 protein expression by MECs and DCIS ( P <0.0001) and between high expression level and presence of invasion ( P =0.006) in DCIS. Other validated alterations in MEC expression profile included upregulation of Nephronectin and downregulation of parathyroid hormone like hormone ( PTHLH ), fibroblast growth factor receptor 2 ( FGFR2 ), ADAMTS5 , TGFBR3 , and CAV1 . In vitro experiments revealed downregulation of PTHLH in DCIS-modified MECs versus normal lines when cultured on Fibronectin matrix. This is the first study to use this in vivo technique to investigate molecular changes in MECs in DCIS. This study adds more evidences to the molecular deviations in MECs toward tumor progression in DCIS through upregulation of the tumor-promoting molecules that may lead to novel predictive and therapeutic targets.

Clinical Significance of Immunohistochemical Expression of Neuropeptide Y1 Receptor in Patients With Breast Cancer in Egypt.

Breast cancer (BC) is the most common malignancy in female individuals worldwide. It constitutes about 38.8% of all malignant tumors among Egyptian female individuals. Neuropeptide Y1 receptor (NPY1R) is one of the most abundant peptides in the central and peripheral nervous systems of mammals. It has been found to promote proliferation, vascularization, and stimulate migration in several cell types and tissues and some types of tumor. This the first immunohistochemical study to evaluate the expression of NPY1R in BC and its correlation with clinicopathologic parameters and patient survival. This study included 92 patients with BC. Immunohistochemical staining for NPY1R was done on paraffin-embedded formalin-fixed tissue sections. Statistically significant increases in NPY1R expression was seen in malignant (46/92; 50%) versus non-neoplastic tissue (12/29; 20.7%) (P<0.001). The receiver operating characteristic curve showed that NPY1R is a poor diagnostic test for BC (P<0.001, area under the curve=0.686) in breast tissue. Membranous was the most common pattern of positivity in carcinoma cases (24/46; 52.2%). Statistically significant associations were found between positive NPY1R expression and the presence of metastatic disease (P<0.001), clinical stage (P=0.0003), perineurial invasion (P=0.003), estrogen receptor expression (P=0.004), molecular subtype (P=0.015), Nottingham Prognostic Index risk group (P=0.04), radiotherapy treatment (P=0.01), hormonal treatment (P=0.015), and type of endocrine therapy (P=0.011). Although no significant association was detected between NPY1R-positive and NPY1R-negative cases regarding overall survival and progression-free survival, cases with non-nuclear (membranous+cytoplasmic) expression showed near significantly shorter survival (P=0.063). This study shows that NPY1R was identified in about 50% of malignant BC cases. Its expression correlates with some features of the aggressive disease being associated with metastasis, perineurial invasion, advanced stages, and poor Nottingham Prognostic Index. This suggests a potential prognostic role of NPY1R in BC. Non-nuclear expression of NPY1R seems to be more important in terms of prognosis of BC.

Immunohistochemical Expression of Microfibrillar-associated Protein 5 (MFAP5) in Invasive Breast Carcinoma of No Special Type.

Breast cancer (BC) remains the most prevalent female cancer in Egypt and worldwide. Microfibrillar-associated protein 5 (MFAP5) is a multifunctional glycoprotein. Although MFAP5 gene was among the genes that found globally expressed in human cancers, it had been only recently reported in few cancer research studies. This is a retrospective study that has been conducted on 66 Egyptian patients who had invasive carcinoma of no special type. Immunohistochemical staining for MFAP5 was applied on the archival formalin-fixed paraffin-embedded blocks. Staining was assessed semiquantitatively and correlated with the available clinicopathologic parameters and immunohistochemical subtypes of BC. MFAP5 epithelial cytoplasmic expression was observed in 89.4% (59/66) of cases. In contrast, nuclear expression was seen in non-neoplastic breast lobules and premalignant lesions adjacent to tumors that also exhibited constant staining in myoepithelial layer. Statistical analysis of epithelial cytoplasmic expression revealed association of MFAP5 expression with tumor size (P=0.046), high histologic grade (P=0.007), presence of lymph node metastasis (P=0.014), poor Nottingham Prognostic Index (NPI) (P=0.001), late stage (P=0.008), immunohistochemical subtypes of BC (P=0.018), and increased microvessel density using CD34 immunostianing (P=0.04). MFAP5 cytoplasmic expression was also observed in an adjacent duct carcinoma in situ component in 37/45 cases (82.2%). This study showed that MFAP5 is a novel myoepithelial cell marker that appears to be upregulated in duct epithelium in duct carcinoma in situ and invasive carcinoma of no special type during tumorogenesis and that its cytoplasmic expression in invasive tumors seems to have a poor prognostic role manifested by its association with poor prognostic parameters such as high grade, late stage, lymph node invasion, and increased microvessel density.

The Prognostic Role of Ezrin and HER2/neu Expression in Osteosarcoma.

Osteosarcoma is the most common primary malignant bone tumor in Egypt. Ezrin is involved in cell adhesion to the extracellular matrix and in cell-cell interactions facilitating metastasis. HER2/neu is overexpressed in breast cancer and other types of cancer. This study aimed to assess the expression of ezrin and HER2/neu in 57 primary osteosarcoma cases and to correlate their expression with the available clinicopathologic parameters and the overall, metastasis-free and event-free survival. Both ezrin and HER2/neu were not expressed in the normal bone and they were upregulated in 82.5% and 71.9% of osteosarcoma, respectively. Positive ezrin expression was significantly associated with young age (below 25 y) (P=0.01), high grade (P=0.001), and short survival time (P=0.0001). Positive HER2/neu expression was significantly associated with high-grade osteosarcoma (P=0.04). Membranous HER2/neu expression was the only factor that showed significant impact on metastasis-free (P=0.002) and event-free survival (P=0.002). Ezrin was significantly correlated with HER2/neu expression (P=0.02). Advanced stage (P=0.0001), metastasis (P=0.0001), and recurrence (P=0.01) were the factors affecting the overall survival of osteosarcoma patients. Ezrin and HER2/neu are overexpressed and coexpressed in osteosarcoma with adverse prognostic features such as high grade. Membranous pattern of HER2/neu seems to be more important than the cytoplasmic pattern because of its impact on metastasis-free and event-free survival. Therefore, ezrin and HER2/neu could be potential prognostic markers and treatment targets for osteosarcoma.

Altered microenvironment promotes progression of preinvasive breast cancer: myoepithelial expression of αvß6 integrin in DCIS identifies high-risk patients and predicts recurrence.

PURPOSE: This study investigated the functional and clinical significance of integrin αvß6 upregulation in myoepithelial cells of ductal carcinoma in situ (DCIS). EXPERIMENTAL DESIGN: Archival samples of DCIS and DCIS with associated invasion (n = 532) were analyzed for expression of αvß6 by immunohistochemistry and ability to predict recurrence and progression assessed in an independent, unique cohort of DCIS cases with long-term follow-up. Primary myoepithelial cells and myoepithelial cell lines, with and without αvß6 expression, were used to measure the effect of αvß6 on growth and invasion of tumor cell lines in vitro and in a xenograft mouse model. Involvement of TGFß signaling was established using mink lung epithelial cell (MLEC) assay and antibody inhibition, and expression and activation of matrix metalloproteinase (MMP)-9 established by Real Time-PCR and zymography. RESULTS: Expression of αvß6 is significantly associated with progression to invasive cancer (P < 0.006) and with recurrence over a median follow-up of 114 months in a series of matched DCIS cases treated with local excision. We show that expression of αvß6 drives myoepithelial cells to promote tumor cell invasion in vitro and enhances mammary tumor growth in vivo. The tumor-promoting effect of αvß6-positive myoepithelial cells is dependent on TGFß-driven upregulation of MMP9 and can be abrogated by inhibiting this pathway. CONCLUSION: These findings indicate that altered myoepithelial cells in DCIS predict disease progression and recurrence and show that upregulation of αvß6 on myoepithelial cells generates a tumor promoter function through TGFß upregulation of MMP-9. These data suggest that expression of αvß6 may be used to stratify patients with DCIS.