Crosstalk between progesterone receptor membrane component 1 and estrogen receptor α promotes breast cancer cell proliferation.

Progesterone (P4) and estradiol (E2) have been shown to stimulate and regulate breast cancer proliferation via classical nuclear receptor signaling through progesterone receptor (PR) and estrogen receptor α (ERα), respectively. However, the basis of communication between PR/ERα and membrane receptors remains largely unknown. Here, we aim to identify classical and nonclassical endocrine signaling mechanisms that can alter cell proliferation through a possible crosstalk between PR, ERα, and progesterone receptor membrane component 1 (PGRMC1), a membrane receptor frequently observed in breast cancer cells. While P4 and E2 treatment increased cell proliferation of ER+/PR+/PGRMC1 overexpressing breast cancer cells, silencing ERα and PR or treatment with selective estrogen receptor modulator (SERM) tamoxifen, or (PR-antagonist) RU-486 decreased cell proliferation. All four treatments rapidly altered PGRMC1 mRNA levels and protein expression. Furthermore, P4 and E2 treatments rapidly activated EGFR a known interacting partner of PGRMC1 and its downstream signaling. Interestingly, downregulation of ERα by tamoxifen and ERα silencing decreased the expression levels of PGRMC1 with no repercussions to PR expression. Strikingly PGRMC1 silencing decreased ERα expression irrespective of PR. METABRIC and TCGA datasets further demonstrated that PGRMC1 expression was comparable to that of ERα in Luminal A and B breast cancers. Targeting of PR, ERα, and PGRMC1 confirmed that a crosstalk between classical and nonclassical signaling mechanisms exists in ER+ breast cancer cells that could enhance the growth of ER+/PR+/PGRMC1 overexpressing tumors.

Progesterone receptor membrane component 1 promotes the growth of breast cancers by altering the phosphoproteome and augmenting EGFR/PI3K/AKT signalling.

BACKGROUND: Increased expression of the progesterone receptor membrane component 1 (PGRMC1) has been linked to multiple cancers, including breast cancer. Despite being a regulatory receptor and a potential therapeutic target, the oncogenic potential of PGRMC1 has not been studied. METHODS: The impact of PGRMC1 on breast cancer growth and progression was studied following chemical inhibition and alteration of PGRMC1 expression, and evaluated by using online-based gene expression datasets of human breast cancer tissue. MTS, flow cytometry, qPCR, Western blotting, confocal microscopy and phosphoproteome analysis were performed. RESULTS: We observed higher PGRMC1 levels in both ER-positive ZR-75-1 and TNBC MDA-MB-468 cells. Both chemical inhibition and silencing decreased cell proliferation, induced cell-cycle arrest, promoted apoptosis and reduced the migratory and invasive capabilities of ZR-75-1 and MDA-MB-468 cells. Further, phosphoproteome analysis demonstrated an overall decrease in activation of proteins involved in PI3K/AKT/mTOR and EGFR signalling pathways. In contrast, overexpression of PGRMC1 in non-malignant MCF10A cells resulted in increased cell proliferation, and enhanced activity of PI3K/AKT/mTOR and EGFR signalling pathways. CONCLUSIONS: Our data demonstrate that PGRMC1 plays a prominent role in regulating the growth of cancer cells by altering the PI3K/AKT/mTOR and EGFR signalling mechanisms in both ER-positive and TNBC cells.

The association between metabolic syndrome and Hepatitis C virus infection in the United States.

PURPOSE: Hepatitis C virus (HCV) infection is the prevalent risk factor for chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) worldwide. The association between metabolic syndrome (MetS) and HCV infection has not been studied effectively, particularly among different ethnic/racial groups in the US. METHODS: A retrospective cross-sectional study was conducted using data from the National Health and Nutrition Examination Survey (1999-2014). Unadjusted and adjusted associations were summarized using the prevalence ratio (PR) and 95% confidence interval (CI) after exploring possible interactions. RESULTS: In the overall population, MetS was significantly associated with HCV infection with an interaction of age. After adjusting for all potential confounders, MetS was found to be significantly associated with HCV among non-obese and younger adults of age less than 60 years (PR 1.67, 95% CI 1.21-2.30, p = 0.002). MetS was also associated with an increased prevalence of HCV in each racial/ethnic group, while the association was strongly modified by age and obesity status of the subjects in different ethnic/racial groups. CONCLUSIONS: MetS or its components are associated with an increased prevalence of HCV in some sub-populations of all ethnic/racial groups in the US. A better understanding of the pathophysiology of MetS associated with HCV is important as MetS may have a role in HCV infection treatment outcomes.

The Prevalence of Genital Human Papillomavirus Subtypes in a Cohort of Hispanic Women Presenting for Cervical Cancer Screening Along the US-Mexico Border.

Introduction : Hispanic women residing along the US-Mexico border have the highest cervical cancer incidence rates in the US. Genital human papillomavirus (HPV) is the major causative agent, but more information is needed about the prevalence and distribution of genital HPV subtypes in this high-risk population. Methods : A population-based cross-sectional study of uninsured Hispanic women along the US-Mexico border was conducted and participants had their cervical specimens undergo DNA extraction followed by HPV genotype testing using the Linear Assay from Roche® Diagnostics, to identify 37 genital HPV subtypes. Results : Among the 585 women aged 21-65 years, 584 self-identfied as Hispanic. Any HPV subtype prevalence was 53.2% (95% CI: 49.0%-57.3%) and of these 52% (i.e. 27.5% of the total) had single infections and 48% (i.e. 25.6% of the total) had multiple infections. High-risk HPV prevalence was 15.6% (95% CI: 24-31.3%). The mean number of subtypes among those testing positive was 2.1 (SD 1.6). The prevalence of any HPV and high-risk HPV showed a U shaped pattern with age; and prevalence of 16/18 and non-16/18 high-risk subtypes (e.g. 31, 33, 35, 39, 45, 51, 52, 58); also varied with age. Forty-one percent of high-risk HPV occurrences were of a subtype not covered by the current nonavalent HPV vaccine. Discussion : Our findings suggest a different high-risk HPV subtype pattern and age distribution among Hispanic women in the USA, which could have implications for future cervical cancer prevention strategies.

The Association of Background Parenchymal Enhancement at Breast MRI with Breast Cancer: A Systematic Review and Meta-Analysis.

BackgroundThe higher level of background parenchymal enhancement (BPE) at breast MRI has the potential for early detection and prediction of the risk of breast cancer. However, conflicting findings have been reported about the association between the level of BPE at breast MRI and the presence of breast cancer.PurposeTo evaluate the association between qualitative and quantitative BPE at dynamic contrast material-enhanced MRI and breast cancer among populations with average risk and high risk separately.Materials and MethodsA retrospective meta-analysis of observational studies comparing either qualitative or quantitative assessments of BPE in women with and women without breast cancer was performed for studies published through July 2018. Pooled odds ratios (ORs) or standardized mean differences and 95% confidence intervals (CIs) were estimated by using DerSimonian-Laird random-effects models. The heterogeneity across the studies was measured by using the statistic I 2. Sensitivity analyses were conducted to test this association according to different study characteristics. P values less than or equal to 5% were considered to indicate statistically significant results.ResultsEighteen studies comprising 1910 women with breast cancer and 2541 control participants were included in the analysis. Among women with high risk, at least moderate BPE (OR, 1.6; 95% CI: 1.0, 2.6; P = .04) or at least mild BPE (OR, 2.1; 95% CI: 1.5, 3.0; P < .001) was associated with higher odds of breast cancer. Furthermore, women with breast cancer showed a higher average BPE percentage compared with control participants with high risk (standardized mean difference, 0.5; 95% CI: 0.2, 0.9; P = .001). No association was observed between at least mild BPE level (P = .15) or at least moderate BPE level (P = .38) and the presence of breast cancer among the population with average risk.ConclusionA higher level of background parenchymal enhancement measured at breast MRI is associated with the presence of breast cancer in women with high risk, but not in women with average risk.© RSNA, 2019Online supplemental material is available for this article.See also the editorial by Mann and Pinker in this issue.

Glucose insult elicits hyperactivation of cancer stem cells through miR-424-cdc42-prdm14 signalling axis.

BACKGROUND: Meta-analysis shows that women with diabetes have a 20% increased risk of breast cancer and also an increased risk for distant metastasis and mortality. The molecular mechanisms for distant metastasis and mortality in breast cancer patients with diabetes are not very well understood. METHODS: We compared the effect of physiological (5 mM) and diabetic (10 mM) levels of glucose on malignant breast epithelial cell invasion and stemness capabilities. We performed microRNA array to determine the dysregulated microRNAs in hyperglycaemic conditions and performed functional and molecular analysis of the gene targets. RESULTS: Hyperglycaemia leads to hyperactivation of cancer stem cell pool and enhances invasive ability of breast cancer cells. MiR-424 seems to be a key regulator of cancer cell stemness and invasion. Knockdown of miR-424 in cancer cells under euglycaemic conditions leads to enhanced invasion and stem cell activity, whereas ectopic expression of miR-424 in cancer cells under hyperglycaemic conditions results in suppressed invasion and stem cell activity. Cdc42, a target of miR-424, influences cancer stem cell activity by positively regulating prdm14 through activation of pak1 (p-21-activated kinase 1) and stat5. CONCLUSIONS: Our findings establish miR-424→︀cdc42→︀prdm14 axis as a key molecular signalling cascade that might influence breast cancer progression in diabetic patients through hyperactivation of cancer stem cells.

Desacetyl nimbinene inhibits breast cancer growth and metastasis through reactive oxygen species mediated mechanisms.

Accumulation of reactive oxygen species (ROS) has been implicated in induction of apoptosis and regulation of key signaling molecules in cancer cells. Phytochemicals are potent source of anticancer drugs as wells as potential inducers of ROS. Neem (Azadirachta indica) is a medicinal plant used for the treatment of various diseases. The main objective of this study is to investigate the anticancer effect of desacetyl nimbinene (DAN; an active ingredient of neem) against breast cancer. Normal and breast cancer cell lines were used for the study. The effect of DAN on cell proliferation, apoptosis, ROS generation, migration, and invasion was analyzed. Antioxidant enzymes superoxide dismutase (SOD)1 and SOD2 were overexpressed to test the effect of DAN-induced ROS generation on breast cancer growth. Key survival and apoptotic protein markers were analyzed to validate the anticancer effect of DAN. Our data demonstrated that DAN inhibited the growth of breast cancer cells by inducing ROS generation. Further investigations revealed that DAN treatment lead to the loss of mitochondrial membrane potential resulting in mitochondria-dependent apoptotic cell death. Increased phosphorylation of c-Jun-N-terminal kinase (JNK) and reduced phosphorylation of p38 were also observed in response to DAN treatment. Inhibition of ROS production by overexpressing antioxidant enzymes SOD1 and SOD2 reduced the DAN-induced cytotoxicity. Additionally, DAN significantly inhibited migration and invasion of MDA-MB-231 breast cancer cells. Overall, our data suggest that DAN exerts its anticancer effect on breast cancer by induction of mitochondria-mediated apoptosis mediated by ROS accumulation.

Receptor activator for nuclear factor-κB ligand signaling promotes progesterone-mediated estrogen-induced mammary carcinogenesis.

Breast cancer is a leading cause of cancer-related death in women. Prolonged exposure to the ovarian hormones estrogen and progesterone increases the risk of breast cancer. Although estrogen is known as a primary factor in mammary carcinogenesis, very few studies have investigated the role of progesterone. Receptor activator for nuclear factor-κB (NF-κB) ligand (RANKL) plays an important role in progesterone-induced mammary carcinogenesis. However, the molecular mechanism underlying RANKL-induced mammary carcinogenesis remains unknown. In our current study, we show that RANKL induces glioma-associated oncogene homolog 1 (GLI-1) in estrogen-induced progesterone-mediated mammary carcinogenesis. In vivo experiments were carried out using ACI rats and in vitro experiments were carried out in MCF-7 cells. In ACI rats, mifepristone significantly reduced the incidence of mammary tumors. Likewise, mifepristone also inhibited the proliferation of MCF-7 cells. Hormone treatments induced RANKL, receptor activator of NF-κB (RANK), and NF-κB in a protein kinase B-dependent manner and inhibited apoptosis by activation of anti-apoptotic protein Bcl2 in mammary tumors and MCF-7 cells. Mechanistic studies in MCF-7 cells reveal that RANKL induced upstream stimulatory factor-1 and NF-κB, resulting in subsequent activation of their downstream target GLI-1. We have identified that progesterone mediates estrogen-induced mammary carcinogenesis through activation of GLI-1 in a RANKL-dependent manner.

A Breast Tissue Protein Expression Profile Contributing to Early Parity-Induced Protection Against Breast Cancer.

BACKGROUND/AIMS: Early parity reduces breast cancer risk, whereas, late parity and nulliparity increase breast cancer risk. Despite substantial efforts to understand the protective effects of early parity, the precise molecular circuitry responsible for these changes is not yet fully defined. METHODS: Here, we have conducted the first study assessing protein expression profiles in normal breast tissue of healthy early parous, late parous, and nulliparous women. Breast tissue biopsies were obtained from 132 healthy parous and nulliparous volunteers. These samples were subjected to global protein expression profiling and immunohistochemistry. GeneSpring and MetaCore bioinformatics analysis software were used to identify protein expression profiles associated with early parity (low risk) versus late/nulliparity (high risk). RESULTS: Early parity reduces expression of key proteins involved in mitogenic signaling pathways in breast tissue through down regulation of EGFR1/3, ESR1, AKT1, ATF, Fos, and SRC. Early parity is also characterized by greater genomic stability and reduced tissue inflammation based on differential expression of aurora kinases, p53, RAD52, BRCA1, MAPKAPK-2, ATF-1, ICAM1, and NF-kappaB compared to late and nulli parity. CONCLUSIONS: Early parity reduces basal cell proliferation in breast tissue, which translates to enhanced genomic stability, reduced cellular stress/inflammation, and thus reduced breast cancer risk.

Recurrence and metastasis of breast cancer is influenced by ovarian hormone's effect on breast cancer stem cells.

Cancer stem cells (CSCs) have recently attracted great interest because of their emerging role in initiation, progression and metastasis, combined with their intrinsic resistance to chemotherapy and radiation therapy. CSCs and its interaction with hormones in breast cancer are currently being investigated with the aim of uncovering the molecular mechanisms by which they evade conventional treatment regimens. In this review, we discuss recent experimental data and new perspectives in the area of steroid hormones and their cross-talk with breast CSCs. We have covered literature associated with biomarkers, hormone receptors and hormone responsive signaling pathways in breast CSC. In addition, we also discuss the role of miRNAs in hormone mediated regulation of breast CSCs.

Parity and short-term estradiol treatment utilizes similar cellular mechanisms to confer protection against breast cancer.

BACKGROUND: Protective effect of early pregnancy and short-term estrogen treatment (STET), against breast cancer is well established. The underlying mechanisms are not well understood. In this study, we compared the mammary gland cellular microenvironment influenced/induced by parity and STET alongside age-matched controls. METHODS: Parous, STET, and control rats were injected with N-methyl-N-nitrosourea at 15 weeks and monitored for the development of mammary cancer. A subset of 4 rats were killed five weeks post carcinogen treatment and mammary gland samples were isolated and subjected to molecular analysis. RESULTS: Our results demonstrated a reduction in cell survival, extracellular matrix associated proliferation, hormonal and growth factor receptor pathways in the experimental groups compared to control rats. Moreover, concomitant reductions in the EMT markers along with cell migration regulators were also observed in parous and STET groups. Hormonal receptor such as GHR, PR, ERα and growth factor receptors IGFR, EGFR and erbB2 were down regulated in the treatment groups. Further analysis revealed that parity and STET drastically reduced the expression, activation of JAK2 and nuclear localization of STATs. CONCLUSION: Parity and STET by targeting major cell signaling pathways involved in cell survival, cell migration and cell death reduces the mammary tumor promoting environment.

Activation of AKT signaling promotes epithelial-mesenchymal transition and tumor growth in colorectal cancer cells.

Activation of the serine-threonine protein kinase AKT has emerged as a central feature of epithelial-mesenchymal transition (EMT), which is the initial step for metastasis in many cancer models, including colorectal cancer. The focus of our study was to dissect the role of AKT and its molecular regulation of EMT in colorectal cancer. HCT-116 colorectal cancer cells stably overexpressing AKT (AKT/HCT-116) showed significantly higher cell proliferation compared with vector-transfected cells (pCMV/HCT-116). Elevated expression of important EMT-related transcription factors and genes such as Snail, Slug, ß-catenin, vimentin, and MMP-9 correlated with increased migration and invasion by AKT/HCT-116 cells. Further, in vivo studies confirmed that AKT/HCT-116 xenografts were highly aggressive and angiogenic in nature compared with pCMV/HCT-116 xenografts. Molecular analysis of tumor samples revealed transcriptional regulation of Snail, Slug, ß-catenin, MMP-2, and MMP-9 in AKT/HCT-116 tumors. These results were supported by immunohistochemistry analysis. Low levels of E-cadherin expression with a concomitant increase in and nuclear localization of ß-catenin were evident in AKT/HCT-116 tumors compared with control tumors. Increased microvessel formation coincident with high expression of Factor VIII and increased numbers of reticulocytes confirmed the angiogenic property of AKT/HCT-116 tumors. Our results confirm the potential role of AKT signaling in regulating EMT and angiogenesis in colorectal cancer and suggest that inhibition of AKT can serve as an important therapeutic strategy in modulating EMT in colorectal cancer growth and metastasis.

The role of hormones and aromatase inhibitors on breast tumor growth and general health in a postmenopausal mouse model.

BACKGROUND: Breast cancer is the most frequently diagnosed cancer in women in the United States. Approximately 70% of breast cancers are diagnosed in postmenopausal women. Major clinical trials and experimental studies showed that aromatase inhibitors are effective against postmenopausal breast cancer. Despite their effectiveness in reducing tumor recurrence, aromatase inhibitors have adverse effects on the cardiovascular system and increase osteoporosis and bone fractures. Our study is aimed at investigating the role of natural steroid hormones on serum cardiovascular and bone resorption markers in an established mouse model mimicking postmenopausal breast cancer. METHODS: Ovariectomized nude mice were transplanted with MCF-7 breast cancer cells constitutively expressing aromatase. The mice were treated with different combinations and doses of steroids, [estrogen (25 pg, 40 pg, 100 pg), progesterone (6 ng) and testosterone (50 ng)] along with dehydroepiandrostenedione (100 ug). Serum levels of HDL, LDL/VLDL, free and total cholesterol, total and bone specific alkaline phosphatase and triglycerides were analyzed after 5, 10 and 15 months. RESULTS: Free cholesterol and LDL/VLDL levels in serum were reduced in groups mimicking estrous cycle and menstrual cycle hormones treatment. HDL cholesterol was increased in all the hormone treated groups except the estrous cycle-mimicking group. Bone specific alkaline phosphatase was decreased in menstrual cycle levels of estrogen and progesterone treatment. CONCLUSIONS: All together our results show that use of natural hormones in appropriate combinations have beneficial effects on cardiac and bone toxicity, along with better tumor reduction than current treatments.

microRNA alterations in ALDH positive mammary epithelial cells: a crucial contributing factor towards breast cancer risk reduction in case of early pregnancy.

BACKGROUND: microRNAs have recently succeeded in grabbing the center stage in cancer research for their potential to regulate vital cellular process like cell cycle, stem cell renewal and epithelial mesenchymal transition. Breast cancer is the second most leading cause of cancer related mortality in women. The main reason for mortality is chemoresistance and metastasis for which remnant stem cells are believed to be the cause. One of the natural ways to reduce the risk of breast cancer in women is early pregnancy. Unraveling the mechanism behind it would add to our knowledge and help in evolving newer paradigms for breast cancer prevention.The current study deals with investigating transcriptomic differences in putative stem cells in mammary epithelial cell population (MECs) in terms of genes and microRNAs. In silico tools were used to identify potential mechanisms. ALDH positive MECs represent a putative stem cell population in the mammary gland. METHODS: MECs were extracted from the mammary gland of virgin and parous (one time pregnant) rats. ALDH positive MECs were sorted and used for transcriptional and translational analysis for genes and microRNAs. In silico analysis for target prediction and networking was performed through online portals of Target Scan and Metacore. RESULTS: A total of 35 and 49 genes and microRNAs respectively were found to be differentially expressed within the two groups. Among the important genes were Lifr, Acvr1c, and Pparγ which were found to be targeted by microRNAs in our dataset like miR-143, miR-30, miR-140, miR-27b, miR-125a, miR-128ab, miR-342, miR-26ab, miR-181, miR-150, miR-23ab and miR-425. In silico data mining and networking also demonstrates that genes and microRNA interaction can have profound effects on stem cell renewal, cell cycle dynamics and EMT processes of the MEC population. CONCLUSIONS: Our data clearly shows that certain microRNAs play crucial role in the regulation of ALDH positive MECs and favor an anti-carcinogenic environment in the post-partum gland. Some of the potential interplaying mechanisms in the ALDH positive MEC population identified through this study are p21, Lifr and Pparγ mediated cell cycle regulation, regulation of metastasis and expansion of stem cell pool respectively.

A genomics approach to identify susceptibilities of breast cancer cells to "fever-range" hyperthermia.

BACKGROUND: Preclinical and clinical studies have shown for decades that tumor cells demonstrate significantly enhanced sensitivity to "fever range" hyperthermia (increasing the intratumoral temperature to 42-45°C) than normal cells, although it is unknown why cancer cells exhibit this distinctive susceptibility. METHODS: To address this issue, mammary epithelial cells and three malignant breast cancer lines were subjected to hyperthermic shock and microarray, bioinformatics, and network analysis of the global transcription changes was subsequently performed. RESULTS: Bioinformatics analysis differentiated the gene expression patterns that distinguish the heat shock response of normal cells from malignant breast cancer cells, revealing that the gene expression profiles of mammary epithelial cells are completely distinct from malignant breast cancer lines following this treatment. Using gene network analysis, we identified altered expression of transcripts involved in mitotic regulators, histones, and non-protein coding RNAs as the significant processes that differed between the hyperthermic response of mammary epithelial cells and breast cancer cells. We confirmed our data via qPCR and flow cytometric analysis to demonstrate that hyperthermia specifically disrupts the expression of key mitotic regulators and G2/M phase progression in the breast cancer cells. CONCLUSION: These data have identified molecular mechanisms by which breast cancer lines may exhibit enhanced susceptibility to hyperthermic shock.

Associations of sex hormone ratios with metabolic syndrome and inflammation in US adult men and women.

Background: Sex hormones play a critical role in sex differences and cardiovascular disease risk associated with metabolic syndrome (MS) and inflammation. However, the associations of sex hormone ratios with metabolic and inflammatory markers are unclear according to sex and age differences. We evaluated the associations of sex hormone ratios with MS and inflammation among males and females. Methods: A retrospective cross-sectional study was conducted by including all adults from the National Health and Nutrition Examination Survey cycles 2013-2016 and excluding any pregnant women, heart disease, diabetes, and those currently taking insulin. MS was defined using the National Cholesterol Education Program criteria and a high-sensitivity C-reactive protein (CRP) level>3 mg/L was defined as a high CRP. Measures of MS components and CRP concentrations were also analyzed. The primary exposures were testosterone to estradiol (excess androgen index), testosterone to sex hormone-binding globulin (free androgen index), and estradiol to sex hormone-binding globulin (free estradiol index). The adjusted associations were summarized with a relative risk (RR) and 95% confidence interval (CI). Results: This study included 9167 subjects with 4360 males and 4807 females. Increases in free estradiol index were positively associated with MS (RR=1.48; 95%CI: 1.39, 1.58; RR=1.31; 95%CI: 1.22, 1.40) and high CRP (RR=1.49; 95%CI: 1.25, 1.77; RR=1.26; 95%CI: 1.06, 1.50) in men with age<50 years and age≥50 years, respectively. Similarly, higher free estradiol index was also robustly associated with increased prevalence of MS (RR=1.22; 95%CI: 1.15, 1.28) and high CRP (RR=1.68; 95%CI: 1.48, 1.90) in women with age ≥50 years. Among women with age<50 years, a higher free androgen index was associated with MS (RR=1.34; 95%CI: 1.25, 1.42) and high CRP (RR=1.13; 95%CI: 1.02, 1.25). These associations were unchanged even after adjusting for all sex hormones. Conclusion: Free estradiol index was consistently and positively associated with MS and high CRP in males of all ages and older females. Free androgen index was positively associated with MS and high CRP in females with age<50 years.

Sending a Message: Use of mRNA Vaccines to Target the Tumor Immune Microenvironment.

While cancer immunotherapies have become central to treatment, challenges associated with the ability of tumors to evade the immune system remain significant obstacles. At the heart of this issue is the tumor immune microenvironment, the complex interplay of the tumor microenvironment and the immune response. Recent advances in mRNA cancer vaccines represent major progress towards overcoming some of the challenges posed by deleterious components of the tumor immune microenvironment. Indeed, major breakthroughs in mRNA vaccine technology, such as the use of replacement nucleotides and lipid nanoparticle delivery, led to the vital success of mRNA vaccine technology in fighting COVID-19. This has in turn generated massive additional interest and investment in the platform. In this review, we detail recent research in the nature of the tumor immune microenvironment and in mRNA cancer vaccines and discuss applications by which mRNA cancer vaccines, often in combination with various adjuvants, represent major areas of potential in overcoming tumor immune microenvironment-imposed obstacles. To this end, we also review current mRNA cancer vaccine clinical trials.

Nimbolide Inhibits SOD2 to Control Pancreatic Ductal Adenocarcinoma Growth and Metastasis.

Reactive oxygen species are frequently associated with various cancers including pancreatic ductal adenocarcinomas (PDACs). Superoxide dismutase 2 (SOD2) is an enzyme that plays an important role in reactive oxygen species (ROS) signaling. Investigating the molecular function and biological functions of SOD2 can help us develop new therapeutic options and uncover new biomarkers for PDAC diagnosis and prognosis. Here, we show that nimbolide (NB), a triterpene limonoid, effectively blocks the growth and metastasis of PDACs by suppressing the expression and activity of SOD2. To identify the role of SOD2 in NB-induced anticancer activity, we used RNA interference to silence and plasmid transfection to overexpress it. Silencing SOD2 significantly reduced the growth and metastatic characteristics like epithelial-to-mesenchymal transition, invasion, migration, and colony-forming capabilities of PDACs, and NB treatment further reduced these characteristics. Conversely, the overexpression of SOD2 enhanced these metastatic characteristics. ROS signaling has a strong feedback mechanism with the PI3K/Akt signaling pathway, which could be mediated through SOD2. Finally, NB treatment to SOD2-overexpressing PDAC xenografts resulted in significant inhibition of tumor growth and metastasis. Overall, this work suggests that NB, a natural and safe phytochemical that silences SOD2 to induce high levels of ROS generation, results in increased apoptosis and reduced growth and progression of PDACs. The role of SOD2 in regulating NB-induced ROS generation presents itself as a therapeutic option for PDACs.

Metabolomics of Breast Cancer: A Review.

Breast cancer is the most commonly diagnosed cancer in women worldwide. Major advances have been made towards breast cancer prevention and treatment. Unfortunately, the incidence of breast cancer is still increasing globally. Metabolomics is the field of science which studies all the metabolites in a cell, tissue, system, or organism. Metabolomics can provide information on dynamic changes occurring during cancer development and progression. The metabolites identified using cutting-edge metabolomics techniques will result in the identification of biomarkers for the early detection, diagnosis, and treatment of cancers. This review briefly introduces the metabolic changes in cancer with particular focus on breast cancer.

Both ovarian hormones estrogen and progesterone are necessary for hormonal mammary carcinogenesis in ovariectomized ACI rats.

August-Copenhagen-Irish (ACI) rats are unique in that the ovary-intact females develop high incidence of mammary cancers induced solely by hormones upon prolonged exposure to high levels of estrogen alone. Studies have also shown that such prolonged exposure to high-dose estrogen results in human-like aneuploid mammary cancers in ovary-intact ACI rats. To determine the role of progesterone in mammary carcinogenesis, six-week-old intact and ovariectomized ACI rats were continuously exposed to low- and high-dose estrogen alone, progesterone alone, low-dose estrogen plus progesterone, and ovariectomized ACI rats with high-dose estrogen plus progesterone. Also, ovariectomized ACI rats were treated with high-dose estrogen plus progesterone plus testosterone to determine the role of the androgen, testosterone, if any, in hormonal mammary carcinogenesis. The results indicate that continuous exposure to high, but not low, concentrations of estrogen alone can induce mammary carcinogenesis in intact but not in ovariectomized rats. Mammary carcinogenesis in ovariectomized ACI rats requires continuous exposure to high concentrations of estrogen and progesterone. The addition of testosterone propionate does not affect tumor incidence in such rats. These results suggest that both ovarian hormones estrogen and progesterone are necessary for mammary carcinogenesis induced solely by hormones in ovariectomized ACI rats. Our results are in agreement with the Women's Health Initiative studies, where treatment of postmenopausal women with estrogen (ERT) alone did not increase the risk of breast cancer, but estrogen and progesterone (HRT) did.