Pre-Menopausal Women With Breast Cancers Having High AR/ER Ratios in the Context of Higher Circulating Testosterone Tend to Have Poorer Outcomes

PurposeWomen with breast tumors with higher expression of AR are in general known to have better survival outcomes while a high AR/ER ratio is associated with poor outcomes in hormone receptor positive breast cancers mostly in post menopausal women. We have evaluated the AR/ER ratio in the context of circulating androgens specifically in patients younger than 50 years most of whom are pre-menopausal and hence have a high estrogenic hormonal milieu.MethodsTumor samples from patients 50 years or younger at first diagnosis were chosen from a larger cohort of 270 patients with median follow-up of 72 months. Expression levels of ER and AR proteins were detected by immunohistochemistry (IHC) and the transcript levels by quantitative PCR. Ciculating levels of total testosterone were estimated from serum samples. A ratio of AR/ER was derived using the transcript levels, and tumors were dichotomized into high and low ratio groups based on the third quartile value. Survival and the prognostic significance of the ratio was compared between the low and high ratio groups in all tumors and also within ER positive tumors. Results were further validated in external datasets (TCGA and METABRIC).ResultsEighty-eight (32%) patients were ≤50 years, with 22 having high AR/ER ratio calculated using the transcript levels. Circulating levels of total testosterone were higher in women whose tumors had a high AR/ER ratio (p = 0.02). Tumors with high AR/ER ratio had significantly poorer disease-free survival than those with low AR/ER ratio [HR-2.6 (95% CI-1.02–6.59) p = 0.04]. Evaluation of tumors with high AR/ER ratio within ER positive tumors alone reconfirmed the prognostic relevance of the high AR/ER ratio with a significant hazard ratio of 4.6 (95% CI-1.35–15.37, p = 0.01). Similar trends were observed in the TCGA and METABRIC dataset.ConclusionOur data in pre-menopausal women with breast cancer suggest that it is not merely the presence or absence of AR expression but the relative activity of ER, as well as the hormonal milieu of the patient that determine clinical outcomes, indicating that both context and interactions ultimately influence tumor behavior

PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer

Abstract The PI3K/AKT/mTOR (PAM) signaling pathway is a highly conserved signal transduction network in eukaryotic cells that promotes cell survival, cell growth, and cell cycle progression. Growth factor signalling to transcription factors in the PAM axis is highly regulated by multiple cross-interactions with several other signaling pathways, and dysregulation of signal transduction can predispose to cancer development. The PAM axis is the most frequently activated signaling pathway in human cancer and is often implicated in resistance to anticancer therapies. Dysfunction of components of this pathway such as hyperactivity of PI3K, loss of function of PTEN, and gain-of-function of AKT, are notorious drivers of treatment resistance and disease progression in cancer. In this review we highlight the major dysregulations in the PAM signaling pathway in cancer, and discuss the results of PI3K, AKT and mTOR inhibitors as monotherapy and in co-administation with other antineoplastic agents in clinical trials as a strategy for overcoming treatment resistance. Finally, the major mechanisms of resistance to PAM signaling targeted therapies, including PAM signaling in immunology and immunotherapies are also discussed.

Clinical profile and predictors of visual outcome in nonarteritic anterior ischemic optic neuropathy

Background: Nonarteritic anterior ischemic optic neuropathy (NAION) is a disorder of the optic nerve head causing acute painless visual loss in the elderly. Several ocular and systemic risk factors predispose to optic nerve head ischemia. Patients usually have a moderate visual loss which tends to stabilize in a few months, but complete recovery may not occur. Aim: This study aimed to study the clinical profile of NAION and to find the predictors of visual outcome in the study group. Materials and Methods: This prospective case series study included 25 patients with unilateral acute visual loss and clinical features suggestive of NAION. Detailed history and investigations were done to detect the risk factors implicated for the disease Patients were followed up for 6 months. Initial and final vision were analysed to assess the visual outcome. Statistical analysis was performed using SPSS. Results: Mean age was 58.08 ± 8.118 years. There was no gender predilection. The most common type of disc edema was diffuse hyperemic, and the most common field defect was inferior altitudinal. Systemic comorbid conditions such as dyslipidemia, smoking, hypotension, diabetes, and hypertension had higher odds of developing NAION even though not statistically significant. Correlation between initial vision and visual acuity at 6 months was statistically significant and spontaneous improvement in vision was seen in 16% of patients. Conclusion: Pallid disc edema and poor initial visual acuity were predictors of poor visual outcome. Female gender, hyperemic disc edema, and superior field defect had a favorable outcome. Associated comorbidities increased the risk of visual loss

Data on alteration of hormone and growth factor receptor profiles over progressive passages of breast cancer cell lines representing different clinical subtypes

Human breast cancers are a highly heterogeneous group of tumours consisting of several molecular subtypes with a variable profile of hormone, growth factor receptors and cytokeratins [1]. Here, the data shows immunofluorescence profiling of four different cell lines belonging to distinct clinical subtypes of breast cancer. Post revival, the cell lines were passaged in culture and immunophenotyping was done for ER, HER-2, AR and EGFR. Data for the markers from early passage (5th) through passages as late as 25 for the different cell lines is presented. Keywords: Breast cancer, Cell lines, Immunofluorescenc

Effect of a Novel Sugar Blend on Weight and Cardiometabolic Health among Healthy Indian Adults: A Randomized, Open-Label Study

Obesity is one of the major factors contributing to noncommunicable diseases (NCDs), which is associated with a high intake of a sugar-rich diet. Sugar blend (a novel combination of sugar and stevia) has half the calories of sugar with the same sweetness at recommended use and offers better compliance. A randomized controlled trial was conducted to evaluate the efficacy and safety of this sugar blend in normal to mildly overweight subjects with a body mass index (BMI) of 23–26 kg/m. Sixty subjects were categorized into Group A: Sugar group (n = 30), and Group B: Sugar blend group (n = 30). The primary outcomes evaluated were weight, waist circumference, hip circumference, waist/hip ratio, BMI, and the secondary outcomes evaluated were lipid profile, random blood sugar, and HbA1c. All these parameters were assessed at baseline, 30 days, 60 days, and 90 days. Group B showed a significantly higher weight loss (p = 0.013) at 90 days compared with Group A. A significant reduction in waist circumference (p < 0.0001) by 4.4 cm was noted at 90 days, in addition to reduction in total cholesterol (p < 0.0001), triglyceride (p = 0.006), LDL cholesterol (p = 0.0490), and VLDL cholesterol (p = 0.006) in Group B compared with the baseline. The study revealed that the sugar blend is an effective formulation in reducing weight, anthropometric factors, and other related metabolic parameters. It has been proven to be well tolerated and promotes weight loss when used in conjunction with a daily balanced diet and exercise plan

Cell State Transitions and Phenotypic Heterogeneity in Luminal Breast Cancer Implicating MicroRNAs as Potential Regulators

Luminal breast cancer subtypes respond poorly to endocrine and trastuzumab treatments due to cellular heterogeneity arising from the phenotype transitions, accounted for mainly by the loss of receptor expression. The origins of basal-like and human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer subtypes have been attributed to genetic and protein modifications in stem-like cells and luminal progenitor cell populations, respectively. The post-transcriptional regulation of protein expression is known to be influenced by microRNAs (miRNAs) that are deemed to be master regulators of several biological processes in breast tumorigenesis and progression. Our objective was to identify the fractions of luminal breast cancer cells that share stemness potentials and marker profiles and to elucidate the molecular regulatory mechanism that drives transitions between fractions, leading to receptor discordances. Established breast cancer cell lines of all prominent subtypes were screened for the expression of putative cancer stem cell (CSC) markers and drug transporter proteins using a side population (SP) assay. Flow-cytometry-sorted fractions of luminal cancer cells implanted in immunocompromised mice generated a pre-clinical estrogen receptor alpha (ERα+) animal model with multiple tumorigenic fractions displaying differential expression of drug transporters and hormone receptors. Despite an abundance of estrogen receptor 1 (ESR1) gene transcripts, few fractions transitioned to the triple-negative breast cancer (TNBC) phenotype with a visible loss of ER protein expression and a distinct microRNA expression profile that is reportedly enriched in breast CSCs. The translation of this study has the potential to provide novel therapeutic miRNA-based targets to counter the dreaded subtype transitions and the failure of antihormonal therapies in the luminal breast cancer subtype

miR-18a Mediates Immune Evasion in ER-Positive Breast Cancer through Wnt Signaling

ER-positive (ER+) breast cancer is considered immunologically ‘silent’ with fewer tumor-infiltrating immune cells. We have previously demonstrated the role of miR-18a in mediating invasion and poor prognosis in ER+ breast cancer by activation of the Wnt signaling pathway. Here, we explored the immune-modulatory functions of high levels of miR-18a in these tumors. A microarray-based gene expression analysis performed in miR-18a over-expressed ER+ breast cancer cell lines demonstrated dysregulation and suppression of immune-related pathways. Stratification of the ER+ tumor samples by miR-18a levels in the TCGA and METABRIC cohort and immune cell identification performed using CIBERSORT and Immune CellAI algorithms revealed a higher proportion of T-regulatory cells (p < 0.001) and a higher CD4/CD8 ratio (p < 0.01). miR-18a over-expressed MCF7 co-cultured with THP-1 showed decreased antigen presentation abilities and increased invasiveness and survival. They also promoted the differentiation of pro-tumorigenic M2 macrophages. Inhibition of the Wnt pathway in miR-18a over-expressed cells brought about the restoration of TAP-1, a protein critical for antigen presentation. Examination of tumor specimens from our case series showed that miR-18a high ER+ tumors had a dense lymphocyte infiltrate when compared to miR-18a low tumors but expressed a higher CD4/CD8 ratio and the M2 macrophage marker CD206, along with the invasive marker MMP9. We report for the first time an association between miR-18a-mediated Wnt signaling and stromal immune modulation in ER+ tumors. Our results highlight the possibility of formulating specific Wnt pathway inhibitors that may be used in combination with immune checkpoint blockers (ICB) for sensitizing ‘immune-cold’ ER+ tumors to immunotherapy

Estimation of ALU Repetitive Elements in Plasma as a Cost-Effective Liquid Biopsy Tool for Disease Prognosis in Breast Cancer

Background: Liquid biopsy is widely recognized as an efficient diagnostic method in oncology for disease detection and monitoring. Though the examination of circulating tumor cells (CTC) is mostly implemented for the assessment of genomic aberrations, the need of complex methodologies for their detection has impeded its acceptance in low-resource settings. We evaluated cell-free DNA (cfDNA) as a liquid biopsy tool and investigated its utility in breast cancer patients. Methods: Total cell-free DNA was extracted from the plasma of breast cancer patients (n = 167) with a median follow-up of more than 5 years, at various stages of the disease. Quantitative PCR was performed to estimate the copy numbers of two fractions of ALU repetitive elements (ALU 115 and ALU 247), and DNA integrity (DI) was calculated as the ratio of ALU 247/115. Mutations in TP53 and PIK3CA in the cfDNA were estimated by next-gen sequencing (NGS) in a subset of samples. Associations of the levels of both the ALU fragments with various clinico-pathological factors and disease-free survival at various stages were examined. Nomogram models were constructed with clinical variables and ALU 247 levels to predict disease-free survival and the best performing model was evaluated by decision curve analysis. Results: DI and ALU 247 levels were significantly lower (p p p = 0.005). Higher levels of ALU 247 in the circulation also correlated with low tumor-infiltrating lymphocytes (TIL) within their primary tumors in the ER-negative breast cancer subtype (p = 0.01). Cox proportional hazard analysis confirmed ALU 247 as an independent variable of disease-free survival both in univariate and multivariate analysis [HR 1.3 (95% CI 1.047 to 1.613, p = 0.017)]. The nomogram model showed that the addition of ALU 247 with other variables significantly improved (C-index 0.823) the predictive ability of the model. Conclusion: Our results confirm the utility of cfDNA as an evolving liquid biopsy tool for molecular analysis. Evaluation of larger fragments of cfDNA estimated through ALU 247 can provide vital information concurrent with the pathological process of disease evolution in breast cancer and warrants expansion to other cancer types