Mucins are high molecular weight; multifunctional glycoproteins comprised of two structural classes - the large transmembrane mucins and the gel-forming or secreted mucins. The primary function of mucins is to protect and lubricate the luminal surfaces of epithelium-lined ducts in the human body. Recent studies have identified a differential expression of both membrane bound (MUC1, MUC4 and MUC16) and secreted mucins (MUC2, MUC5AC, MUC5B and MUC6) in breast cancer tissues when compared with the non-neoplastic breast tissues. Functional studies have also uncovered many unique roles of mucins during the progression of breast cancer, which include modulation in proliferative, invasive and metastatic potential of tumor cells. Mucins function through many unique domains those can form complex association with various signaling molecules including growth factor receptors and intercellular adhesion molecules. While there is growing information about mucins in various malignancies including breast cancer, no focused review is there on the expression and functional roles of mucins in breast cancer. In this present review, we have discussed the differential expression and functional roles of mucins in breast cancer. The potential of mucins as diagnostic and prognostic markers and as therapeutic targets in breast cancer have also been discussed.

MUC16/CA125 is a tumor marker currently used in clinics for the follow-up of patients with ovarian cancer. However, MUC16 expression is not entirely restricted to ovarian malignancies and has been reported in other cancers including breast cancer. Although it is well established as a biomarker, function of MUC16 in cancer remains to be elucidated. In the present study, we investigated the role of MUC16 in breast cancer and its underlying mechanisms. Interestingly, our results showed that MUC16 is overexpressed in breast cancer tissues whereas not expressed in non-neoplastic ducts. Further, stable knockdown of MUC16 in breast cancer cells (MDA MB 231 and HBL100) resulted in significant decrease in the rate of cell growth, tumorigenicity and increased apoptosis. In search of a mechanism for breast cancer cell proliferation we found that MUC16 interacts with the ezrin/radixin/moesin domain-containing protein of Janus kinase (JAK2) as demonstrated by the reciprocal immunoprecipitation method. These interactions mediate phosphorylation of STAT3 (Tyr705), which might be a potential mechanism for MUC16-induced proliferation of breast cancer cells by a subsequent co-transactivation of transcription factor c-Jun. Furthermore, silencing of MUC16 induced G2/M arrest in breast cancer cells through downregulation of Cyclin B1 and decreased phosphorylation of Aurora kinase A. This in turn led to enhanced apoptosis in the MUC16-knockdown breast cancer cells through Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated extrinsic apoptotic pathway with the help of c-Jun N-terminal kinase signaling. Collectively, our results suggest that MUC16 has a dual role in breast cancer cell proliferation by interacting with JAK2 and by inhibiting the apoptotic process through downregulation of TRAIL.

IntroductionCurrent studies indicate that triple negative breast cancer (TNBC), an aggressive breast cancer subtype, is associated with poor prognosis and an early pattern of metastasis. Emerging evidence suggests that MUC4 mucin is associated with metastasis of various cancers, including breast cancer. However, the functional role of MUC4 remains unclear in breast cancers, especially in TNBCs.MethodIn the present study, we investigated the functional and mechanistic roles of MUC4 in potentiating pathogenic signals including EGFR family proteins to promote TNBC aggressiveness using in vitro and in vivo studies. Further, we studied the expression of MUC4 in invasive TNBC tissue and normal breast tissue by immunostaining.ResultsMUC4 promotes proliferation, anchorage-dependent and-independent growth of TNBC cells, augments TNBC cell migratory and invasive potential in vitro, and enhances tumorigenicity and metastasis in vivo. In addition, our studies demonstrated that MUC4 up-regulates the EGFR family of proteins, and augments downstream Erk1/2, PKC-γ, and FAK mediated oncogenic signaling. Moreover, our studies also showed that knockdown of MUC4 in TNBC cells induced molecular changes suggestive of mesenchymal to epithelial transition. We also demonstrated in this study, for the first time, that knockdown of MUC4 was associated with reduced expression of EGFR and ErbB3 (EGFR family proteins) in TNBC cells, suggesting that MUC4 uses an alternative to ErbB2 mechanism to promote aggressiveness. We further demonstrate that MUC4 is differentially over-expressed in invasive TNBC tissues compared to normal breast tissue.ConclusionsMUC4 mucin expression is associated with TNBC pathobiology, and its knockdown reduced aggressiveness in vitro, and tumorigenesis and metastasis in vivo. Overall, our findings suggest that MUC4 mucin promotes invasive activities of TNBC cells by altering the expression of EGFR, ErbB2, and ErbB3 molecules and their downstream signaling.

Wound healing starts with the recruitment of inflammatory cells that secrete wound-related factors. This step is followed by fibroblast activation and tissue construction. Sphingosine-1-phosphate (S1P) is a lipid mediator that promotes angiogenesis, cell proliferation, and attracts immune cells. We investigated the roles of S1P in skin wound healing by altering the expression of its biogenic enzyme, sphingosine kinase-1 (SphK1). The murine excisional wound splinting model was used. Sphingosine kinase-1 (SphK1) was highly expressed in murine wounds and that SphK1−/− mice exhibit delayed wound closure along with less angiogenesis and inflammatory cell recruitment. Nanoparticle-mediated topical SphK1 overexpression accelerated wound closure, which associated with increased angiogenesis, inflammatory cell recruitment, and various wound-related factors. The SphK1 overexpression also led to less scarring, and the interaction between transforming growth factor (TGF)-β1 and S1P receptor-2 (S1PR2) signaling is likely to play a key role. In summary, SphK1 play important roles to strengthen immunity, and contributes early wound healing with suppressed scarring. S1P can be a novel therapeutic molecule with anti-scarring effect in surgical, trauma, and chronic wound management.

Introduction Gestational diabetes is a common medical disorder in pregnancy. So long, it has been usually treated by insulin. Now it has been found that oral glibenclamide can be used instead of insulin with similar glycemic control and without any adverse maternal and fetal effect. Methods A comparative study between oral glibenclamide and insulin for the management of gestational diabetes mellitus (GDM) was conducted. It was a prospective randomized study and patients attending the antenatal clinic were screened with 75 gm oral glucose between 20 to 28 weeks and GDM was diagnosed based on WHO criteria of 2 hours blood glucose ≥140 mg/dl. Women with gestational diabetes were given medical nutritional therapy (MNT) for 2 weeks. Out of this, 60 women did not achieve the target blood glucose. The goal of treatment was maintenance of mean plasma glucose (MPG) of about 105 mg%. For this the fasting plasma glucose should be around 90 mg/dl and postprandial peaks around 120 mg/dl. Patients were randomly assigned to receive glibenclamide (group A, n = 30) or insulin (group B, n = 30). In group A, glibenclamide was given 2.5 mg orally in morning and doses were increased weekly by 2.5 mg up to a maximum of 20 mg and doses >7.5 mg were given in two divided doses. In group B, insulin 0.7 units per kilogram of body weight at admission was given subcutaneously three times daily and increased weekly as necessary. Self monitoring of blood glucose with glucometer was done. Blood glucose was also measured from the laboratory every week. Glycosylated hemoglobin (HbA1c) was measured before initiation of therapy and repeated in the third trimester before confinement. Terminations of pregnancy in both the groups were done between 37 and 38 weeks. The infant birth weight, blood glucose and serum bilirubin were also recorded in all cases. Results The present study showed that the two groups had similar glycemic status (fasting blood sugar in group A was 103.5 ± 14.62 mg/dl and postprandial blood sugar was 184.1 ± 20.46 mg/dl whereas in group B it was109.3 ± 19.63 mg/dl and 194.3 ± 18.47mg/dl) at the time of entry into the study. The two groups also showed similar levels of glycemic control just before confinement (fasting blood sugar in group A was 88.23 ± 6.55 mg/ dl and postprandial blood sugar was 122.7 ± 10.3 mg/dl whereas in group B it was 88.17 ± mg/dl and 128 ± 12.38 mg/dl) and there was no significant statistical difference in the two groups (p > 0.05). The perinatal outcomes in both the groups were also nearly same. There was no significant difference in birth weight, blood sugar level of neonates and complications between the two groups. There was no case of macrosomia in the two groups and the number of infants large for gestational age (LGA) was four in group A and two in group B. Hypoglycemia in newborn was slightly higher in the group A compared to group B (4 and 3 respectively). Conclusion From our study, it is evident that the use of oral agents is a pragmatic alternative to insulin therapy in cases of gestational diabetes because of similar glycemic control, ease of administration and better patient compliance due to noninvasive treatment. How to cite this article Mukhopadhyay P, Bag TS, Kyal A, Saha DP, Khalid N. Oral Hypoglycemic Glibenclamide: Can it be a Substitute to Insulin in the Management of Gestational Diabetes Mellitus? A Comparative Study. J South Asian Feder Obst Gynae 2012;4(1):28-31.

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Background With the recent emergence of conjugated bile acids as signaling molecules in cancer, a murine model of obstructive jaundice by cholestasis with long-term survival is in need. Here, we investigated the characteristics of 3 murine models of obstructive jaundice. Methods C57BL/6J mice were used for total ligation of the common bile duct (tCL), partial common bile duct ligation (pCL), and ligation of left and median hepatic bile duct with gallbladder removal (LMHL) models. Survival was assessed by Kaplan-Meier method. Fibrotic change was determined by Masson-Trichrome staining and Collagen expression. Results 70% (7/10) of tCL mice died by Day 7, whereas majority 67% (10/15) of pCL mice survived with loss of jaundice. 19% (3/16) of LMHL mice died; however, jaundice continued beyond Day 14, with survival of more than a month. Compensatory enlargement of the right lobe was observed in both pCL and LMHL models. The pCL model demonstrated acute inflammation due to obstructive jaundice 3 days after ligation but jaundice rapidly decreased by Day 7. The LHML group developed portal hypertension as well as severe fibrosis by Day 14 in addition to prolonged jaundice. Conclusion The standard tCL model is too unstable with high mortality for long-term studies. pCL may be an appropriate model for acute inflammation with obstructive jaundice but long term survivors are no longer jaundiced. The LHML model was identified to be the most feasible model to study the effect of long-term obstructive jaundice.

Background: Compared with their European American (EA) counterparts, African American (AA) women are more likely to die from breast cancer in the United States. This disparity is greatest in hormone receptor-positive subtypes. Here we uncover biological factors underlying this disparity by comparing functional expression and prognostic significance of master transcriptional regulators of luminal differentiation. Experimental Design: Data and biospecimens from 262 AA and 293 EA patients diagnosed with breast cancer from 2001 to 2010 at a major medical center were analyzed by IHC for functional biomarkers of luminal differentiation, including estrogen receptor (ESR1) and its pioneer factors, FOXA1 and GATA3. Integrated comparison of protein levels with networklevel gene expression analysis uncovered predictive correlations with race and survival. Results: Univariate or multivariate HRs for overall survival, estimated from digital IHC scoring of nuclear antigen, show distinct differences in the magnitude and significance of these biomarkers to predict survival based on race: ESR1 [EA HR ¼ 0.47; 95% confidence interval (CI), 0.31-0.72 and AA HR ¼ 0.77; 95% CI, 0.48-1.18]; FOXA1 (EA HR ¼ 0.38; 95% CI, 0.23-0.63 and AA HR ¼ 0.53; 95% CI, 0.31-0.88), and GATA3 (EA HR ¼ 0.36; 95% CI, 0.23-0.56; AA HR ¼ 0.57; CI, 0.56-1.4). In addition, we identify genes in the downstream regulons of these biomarkers highly correlated with race and survival. Conclusions: Even within clinically homogeneous tumor groups, regulatory networks that drive mammary luminal differentiation reveal race-specific differences in their association with clinical outcome. Understanding these biomarkers and their downstream regulons will elucidate the intrinsic mechanisms that drive racial disparities in breast cancer survival.