PGRMC1: a new biomarker for the estrogen receptor in breast cancer

Estrogen receptor (ER) status is a critical biomarker in breast cancer, in large part because the ER is the target of tamoxifen and similar drugs. In the previous issue of Breast Cancer Research, Neubauer and colleagues used a proteomic approach to identify proteins that are differentially regulated by ER in breast tumors. The authors showed that ER-negative tumors have elevated levels of PGRMC1 (progesterone receptor membrane component-1), a hormone receptor component and binding partner for P450 proteins. In contrast, PGRMC1 was phosphorylated in ER-positive tumors. The staining patterns of ER and PGRMC1 were mutually exclusive in breast tumor sections, and PGRMC1 staining was sharply increased in hypoxic areas of the tumor. The results suggest that PGRMC1 is a candidate biomarker for ER status and hypoxia in breast cancer

Multi-Gene Expression Predictors of Single Drug Responses to Adjuvant Chemotherapy in Ovarian Carcinoma: Predicting Platinum Resistance

Despite advances in radical surgery and chemotherapy delivery, ovarian cancer is the most lethal gynecologic malignancy. Standard therapy includes treatment with platinum-based combination chemotherapies yet there is no biomarker model to predict their responses to these agents. We here have developed and independently tested our multi-gene molecular predictors for forecasting patients' responses to individual drugs on a cohort of 55 ovarian cancer patients. To independently validate these molecular predictors, we performed microarray profiling on FFPE tumor samples of 55 ovarian cancer patients (UVA-55) treated with platinum-based adjuvant chemotherapy. Genome-wide chemosensitivity biomarkers were initially discovered from the in vitro drug activities and genomic expression data for carboplatin and paclitaxel, respectively. Multivariate predictors were trained with the cell line data and then evaluated with a historical patient cohort. For the UVA-55 cohort, the carboplatin, taxol, and combination predictors significantly stratified responder patients and non-responder patients (p = 0.019, 0.04, 0.014) with sensitivity = 91%, 96%, 93 and NPV = 57%, 67%, 67% in pathologic clinical response. The combination predictor also demonstrated a significant survival difference between predicted responders and non-responders with a median survival of 55.4 months vs. 32.1 months. Thus, COXEN single- and combination-drug predictors successfully stratified platinum resistance and taxane response in an independent cohort of ovarian cancer patients based on their FFPE tumor samples

Study of intragastric structuring ability of sodium alginate based o/w emulsions under in vitro physiological pre-absorptive digestion conditions

In the present work, the intragastric structuring ability of o/w emulsions either stabilised (1–4%, w/w of sodium alginate (SA)) or structured with sheared ionic gel (1–3%, w/w of SA crosslinked with Ca2+) in the absence (saliva and gastric phases constituted of deionised water) or presence of in vitro pre-absorptive conditions (physiological simulated saliva and gastric fluids) was investigated. Visualisation of the morphological aspects of the gastric chymes, in the absence of multivalent counterions, demonstrated that SA stabilised systems underwent a remarkable swelling in the pH range of 2–3, whilst at the same pH range, ionic SA gel structured systems maintained their major structure configuration. When the aforementioned systems were exposed to physiological intragastric fluids, a reduction of the length and the hydrodynamic volume of the alginate fibres was detected regardless the structuring approach. On their exposure to physiological intragastric conditions (pH = 2), SA stabilised emulsions underwent sol–gel transition achieving a ca. 3- to 4-order increase of storage modulus (at 1 Hz). In the case of ionic sheared gel structured emulsions, exposure to physiological intragastric fluids resulted in a 10-fold reduction ability of their acid structuring ability, most likely due to the dialysis of egg-box dimer conformations by monovalent cations and protons and the sterical hindering of hydrogen bonding of MM and GG sequences under acidic conditions. Using of non-physiological simulated intragastric fluids was associated with overestimated structuring performance of SA regardless its physical state

Modes of Disintegration of Solid Foods in Simulated Gastric Environment

A model stomach system was used to investigate disintegration of various foods in simulated gastric environment. Food disintegration modes and typical disintegration profiles are summarized in this paper. Mechanisms contributing to the disintegration kinetics of different foods were investigated as related to acidity, temperature, and enzymatic effect on the texture and changes in microstructure. Food disintegration was dominated by either fragmentation or erosion, depending on the physical forces acting on food and the cohesive force within the food matrix. The internal cohesive forces changed during digestion as a result of water penetration and acidic and enzymatic hydrolysis. When erosion was dominant, the disintegration data (weight retention vs. disintegration time) may be expressed with exponential, sigmoidal, and delayed-sigmoidal profiles. The different profiles are the result of competition among the rates of water absorption, texture softening, and erosion. A linear-exponential equation was used to describe the different disintegration curves with good fit. Acidity and temperature of gastric juice showed a synergistic effect on carrot softening, while pepsin was the key factor in disintegrating high-protein foods. A study of the change of carrot microstructure during digestion indicated that degradation of the pectin and cell wall was responsible for texture softening that contributed to the sigmoidal profile of carrot disintegration

Digestion of Raw and Roasted Almonds in Simulated Gastric Environment

Knowledge of digestion kinetics of solid foods in human stomach, as affected by food processing methods, is critical in establishing processing conditions at the manufacturing stage to achieve desirable release of nutrients in the gastrointestinal tract. The objective of this study was to investigate how roasting affected disintegration and solid release properties of almond in simulated gastric environment. In vitro trials were performed for raw and roasted almonds by using static soaking method and a model stomach system. The changes in sample weight, dry mass, and moisture during the trials were determined. Both compression and penetration tests were used to investigate the texture of almonds with a focus on the influence of absorption of gastric juice. Light microscopy and transmission electronic microscopy were used to study the change in microstructure of the raw and roasted almonds after simulated digestion. The results suggested that the slow disintegration rate and the high amount of swelling of the almonds in the stomach may contribute to their high satiety property. Roasting significantly improved the disintegration rates of almonds and increased loss of solids during simulated digestion, which is well correlated with the decrease in the rigidity of almond samples after absorbing gastric juice. Microstructure of digested almonds showed breakage and breach of cell walls due to acid hydrolysis. Intercellular and intracellular channels formed in almonds during roasting are important for penetration of gastric juice that may facilitate an effective digestion

Intragastric structuring of anionic polysaccharide kappa-carrageenan filled gels under physiological in vitro digestion conditions

In the present work, sodium alginate (SA), low methoxyl pectin (PEC) and κ-carrageenan (κ-CAR) were evaluated for their intragastric structuring ability by means of light microscopy and dynamic oscillatory rheology. SA and PEC solutions, their Ca2+ complexed gel analogues as well as their binary blends with ionically or thermally set sheared κ-CAR gels, were subjected to in vitro orogastric conditions. SA and PEC – Ca2+ complexed sheared gels exerted the highest vulnerability to digestive fluid exposure due to the dialysis of egg-box dimer structures via proton-calcium exchange. Incorporation of SA and PEC systems to κ-CAR gels prevented the loss of mechanical strength of the gastric gels due to the ability of κ-CAR to undergo spontaneous gelation in the presence of Na+ and K+ ions. Binary blends of SA and PEC – Ca2+ complexed sheared gels with κ-CAR-Ca2+ gels exerted a significantly lower mechanical strength loss sensitivity against pH and counterion composition of the gastric fluids

Recent translational research: microarray expression profiling of breast cancer – beyond classification and prognostic markers?

Genomic expression profiling has greatly improved our ability to subclassify human breast cancers according to shared molecular characteristics and clinical behavior. The logical next question is whether this technology will be similarly useful for identifying the dominant signaling pathways that drive tumor initiation and progression within each breast cancer subtype. A major challenge will be to integrate data generated from the experimental manipulation of model systems with expression profiles obtained from primary tumors. We highlight some recent progress and discuss several obstacles in the use of expression profiling to identify pathway signatures in human breast cancer

Amplification of HER2 is a marker for global genomic instability

<p>Abstract</p> <p>Background</p> <p>Genomic alterations of the proto-oncogene c-erbB-2 (HER-2/neu) are associated with aggressive behavior and poor prognosis in patients with breast cancer. The variable clinical outcomes seen in patients with similar HER2 status, given similar treatments, suggests that the effects of amplification of HER2 can be influenced by other genetic changes. To assess the broader genomic implications of structural changes at the HER2 locus, we investigated relationships between genomic instability and HER2 status in patients with invasive breast cancer.</p> <p>Methods</p> <p>HER2 status was determined using the PathVysion^®assay. DNA was extracted after laser microdissection from the 181 paraffin-embedded HER2 amplified (n = 39) or HER2 negative (n = 142) tumor specimens with sufficient tumor available to perform molecular analysis. Allelic imbalance (AI) was assessed using a panel of microsatellite markers representing 26 chromosomal regions commonly altered in breast cancer. Student t-tests and partial correlations were used to investigate relationships between genomic instability and HER2 status.</p> <p>Results</p> <p>The frequency of AI was significantly higher (<it>P </it>< 0.005) in HER2 amplified (27%) compared to HER2 negative tumors (19%). Samples with HER2 amplification showed significantly higher levels of AI (<it>P </it>< 0.05) at chromosomes 11q23, 16q22-q24 and 18q21. Partial correlations including ER status and tumor grade supported associations between HER2 status and alterations at 11q13.1, 16q22-q24 and 18q21.</p> <p>Conclusion</p> <p>The poor prognosis associated with HER2 amplification may be attributed to global genomic instability as cells with high frequencies of chromosomal alterations have been associated with increased cellular proliferation and aggressive behavior. In addition, high levels of DNA damage may render tumor cells refractory to treatment. In addition, specific alterations at chromosomes 11q13, 16q22-q24, and 18q21, all of which have been associated with aggressive tumor behavior, may serve as genetic modifiers to HER2 amplification. These data not only improve our understanding of HER in breast pathogenesis but may allow more accurate risk profiles and better treatment options to be developed.</p

An integration of complementary strategies for gene-expression analysis to reveal novel therapeutic opportunities for breast cancer

INTRODUCTION. Perhaps the major challenge in developing more effective therapeutic strategies for the treatment of breast cancer patients is confronting the heterogeneity of the disease, recognizing that breast cancer is not one disease but multiple disorders with distinct underlying mechanisms. Gene-expression profiling studies have been used to dissect this complexity, and our previous studies identified a series of intrinsic subtypes of breast cancer that define distinct populations of patients with respect to survival. Additional work has also used signatures of oncogenic pathway deregulation to dissect breast cancer heterogeneity as well as to suggest therapeutic opportunities linked to pathway activation. METHODS. We used genomic analyses to identify relations between breast cancer subtypes, pathway deregulation, and drug sensitivity. For these studies, we use three independent breast cancer gene-expression data sets to measure an individual tumor phenotype. Correlation between pathway status and subtype are examined and linked to predictions for response to conventional chemotherapies. RESULTS. We reveal patterns of pathway activation characteristic of each molecular breast cancer subtype, including within the more aggressive subtypes in which novel therapeutic opportunities are critically needed. Whereas some oncogenic pathways have high correlations to breast cancer subtype (RAS, CTNNB1, p53, HER1), others have high variability of activity within a specific subtype (MYC, E2F3, SRC), reflecting biology independent of common clinical factors. Additionally, we combined these analyses with predictions of sensitivity to commonly used cytotoxic chemotherapies to provide additional opportunities for therapeutics specific to the intrinsic subtype that might be better aligned with the characteristics of the individual patient. CONCLUSIONS. Genomic analyses can be used to dissect the heterogeneity of breast cancer. We use an integrated analysis of breast cancer that combines independent methods of genomic analyses to highlight the complexity of signaling pathways underlying different breast cancer phenotypes and to identify optimal therapeutic opportunities.V Foundation for Cancer Research (Partners in Excellence grant