Proteome-wide association study and functional validation identify novel protein markers for pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy, largely due to the paucity of reliable biomarkers for early detection and therapeutic targeting. Existing blood protein biomarkers for PDAC often suffer from replicability issues, arising from inherent limitations such as unmeasured confounding factors in conventional epidemiologic study designs. To circumvent these limitations, we use genetic instruments to identify proteins with genetically predicted levels to be associated with PDAC risk. Leveraging genome and plasma proteome data from the INTERVAL study, we established and validated models to predict protein levels using genetic variants. By examining 8,275 PDAC cases and 6,723 controls, we identified 40 associated proteins, of which 16 are novel. Functionally validating these candidates by focusing on 2 selected novel protein-encoding genes, GOLM1 and B4GALT1, we demonstrated their pivotal roles in driving PDAC cell proliferation, migration, and invasion. Furthermore, we also identified potential drug repurposing opportunities for treating PDAC. SIGNIFICANCE: PDAC is a notoriously difficult-to-treat malignancy, and our limited understanding of causal protein markers hampers progress in developing effective early detection strategies and treatments. Our study identifies novel causal proteins using genetic instruments and subsequently functionally validates selected novel proteins. This dual approach enhances our understanding of PDAC etiology and potentially opens new avenues for therapeutic interventions.

Inflammatory Cytokines Associated with Obesity, Type-2 Diabetes, and Hypertension Exacerbate Breast Cancer Risk in Underserved African American and Latin American Women.

Background: Comorbid chronic diseases, such as obesity, Type-2 Diabetes (T2D), and hypertension (HTN), are major public health issues and highly prevalent among underserved African Americans (AA) and Latin Americans (LA). Elevated inflammatory cytokines are underlying processes in comorbidities (obesity, T2D, and HTN) that could contribute to tumorigenesis and adverse cancer outcomes. Methods: A panel of 19 cytokines was measured by Luminex assay from 570 AA and LA women's serum samples. The comorbidities and breast cancer information were extracted from our existing clinical database. Comorbidity-associated cytokines were identified by linear regression analysis, and the odds ratios of increasing cytokines for breast cancer were evaluated by Logistic regression. Results: Women with obesity, T2D, and HTN elevated specific groups of cytokines. EGF, MCP1, MDC, MIP-1b, and Groα were independent of T2D and HTN significantly associated with obesity. TGFß1 and TGFß2 were T2D-associated cytokines, and MIB-1b, TNFα, and VEGFα were HTN-associated cytokines. Among those comorbidity-associated cytokines, CXCL1, CCL4, CXCL10, TNFα, TGFß1, and TGFß2 were also significantly associated with breast cancer diagnosed at age < 50. Two or more comorbidities further increased the levels of Groα, MIP-1b, TNFα, and TGFßs. Conclusions: Comorbidity-associate cytokines could augment the risk of breast cancer for AA and LA women.

Correction: Hamilton et al. Receptors for Insulin-Like Growth Factor-2 and Androgens as Therapeutic Targets in Triple-Negative Breast Cancer. Int. J. Mol. Sci. 2017, 18, 2305.

In the original publication [...].

Correction: Wu et al. Expression of MALAT1 Promotes Trastuzumab Resistance in HER2 Overexpressing Breast Cancers. Cancers 2020, 12, 1918.

In the original publication, there was a mistake in Figure 4B as published [...].

Enhanced Chemoprevention of Prostate Cancer by Combining Arctigenin with Green Tea and Quercetin in Prostate-Specific Phosphatase and Tensin Homolog Knockout Mice.

The low bioavailability of most phytochemicals limits their anticancer effects in humans. The present study was designed to test whether combining arctigenin (Arc), a lignan mainly from the seed of Arctium lappa, with green tea (GT) and quercetin (Q) enhances the chemopreventive effect on prostate cancer. We performed in vitro proliferation studies on different cell lines. We observed a strong synergistic anti-proliferative effect of GT+Q+Arc in exposing androgen-sensitive human prostate cancer LNCaP cells. The pre-malignant WPE1-NA22 cell line was more sensitive to this combination. No cytotoxicity was observed in normal prostate epithelial PrEC cells. For an in vivo study, 3-week-old, prostate-specific PTEN (phosphatase and tensin homolog) knockout mice were treated with GT+Q, Arc, GT+Q+Arc, or the control daily until 16 weeks of age. In vivo imaging using prostate-specific membrane antigen (PSMA) probes demonstrated that the prostate tumorigenesis was significantly inhibited by 40% (GT+Q), 60% (Arc at 30 mg/kg bw), and 90% (GT+Q+Arc) compared to the control. A pathological examination showed that all control mice developed invasive prostate adenocarcinoma. In contrast, the primary lesion in the GT+Q and Arc alone groups was high-grade prostatic intraepithelial neoplasia (PIN), with low-grade PIN in the GT+Q+Arc group. The combined effect of GT+Q+Arc was associated with an increased inhibition of the androgen receptor, the PI3K/Akt pathway, Ki67 expression, and angiogenesis. This study demonstrates that combining Arc with GT and Q was highly effective in prostate cancer chemoprevention. These results warrant clinical trials to confirm the efficacy of this combination in humans.

Advancements in small molecule drug design: A structural perspective.

In this review, we outline recent advancements in small molecule drug design from a structural perspective. We compare protein structure prediction methods and explore the role of the ligand binding pocket in structure-based drug design. We examine various structural features used to optimize drug candidates, including functional groups, stereochemistry, and molecular weight. Computational tools such as molecular docking and virtual screening are discussed for predicting and optimizing drug candidate structures. We present examples of drug candidates designed based on their molecular structure and discuss future directions in the field. By effectively integrating structural information with other valuable data sources, we can improve the drug discovery process, leading to the identification of novel therapeutics with improved efficacy, specificity, and safety profiles.

From Interaction to Intervention: How Mesenchymal Stem Cells Affect and Target Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) lacks estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expressions, making targeted therapies ineffective. Mesenchymal stem cells (MSCs) have emerged as a promising approach for TNBC treatment by modulating the tumor microenvironment (TME) and interacting with cancer cells. This review aims to comprehensively overview the role of MSCs in TNBC treatment, including their mechanisms of action and application strategies. We analyze the interactions between MSC and TNBC cells, including the impact of MSCs on TNBC cell proliferation, migration, invasion, metastasis, angiogenesis, and drug resistance, along with the signaling pathways and molecular mechanisms involved. We also explore the impact of MSCs on other components of the TME, such as immune and stromal cells, and the underlying mechanisms. The review discusses the application strategies of MSCs in TNBC treatment, including their use as cell or drug carriers and the advantages and limitations of different types and sources of MSCs in terms of safety and efficacy. Finally, we discuss the challenges and prospects of MSCs in TNBC treatment and propose potential solutions or improvement methods. Overall, this review provides valuable insights into the potential of MSCs as a novel therapeutic approach for TNBC treatment.

Advancing Cancer Research: Insights and Innovations in Pathogenesis and Targeted Therapies.

Cancer is a global health challenge that continues to affect millions of people, despite extensive research efforts [...].

Potential Therapies Targeting the Metabolic Reprogramming of Diabetes-Associated Breast Cancer.

In recent years, diabetes-associated breast cancer has become a significant clinical challenge. Diabetes is not only a risk factor for breast cancer but also worsens its prognosis. Patients with diabetes usually show hyperglycemia and hyperinsulinemia, which are accompanied by different glucose, protein, and lipid metabolism disorders. Metabolic abnormalities observed in diabetes can induce the occurrence and development of breast cancer. The changes in substrate availability and hormone environment not only create a favorable metabolic environment for tumorigenesis but also induce metabolic reprogramming events required for breast cancer cell transformation. Metabolic reprogramming is the basis for the development, swift proliferation, and survival of cancer cells. Metabolism must also be reprogrammed to support the energy requirements of the biosynthetic processes in cancer cells. In addition, metabolic reprogramming is essential to enable cancer cells to overcome apoptosis signals and promote invasion and metastasis. This review aims to describe the major metabolic changes in diabetes and outline how cancer cells can use cellular metabolic changes to drive abnormal growth and proliferation. We will specifically examine the mechanism of metabolic reprogramming by which diabetes may promote the development of breast cancer, focusing on the role of glucose metabolism, amino acid metabolism, and lipid metabolism in this process and potential therapeutic targets. Although diabetes-associated breast cancer has always been a common health problem, research focused on finding treatments suitable for the specific needs of patients with concurrent conditions is still limited. Most studies are still currently in the pre-clinical stage and mainly focus on reprogramming the glucose metabolism. More research targeting the amino acid and lipid metabolism is needed.

Genetic variants in African-American and Hispanic patients with breast cancer.

Breast cancer is a disease with significant health disparity affecting mortality in minority women. The present study examined the genetic makeup of breast cancers in African-American and Hispanic/Latinx patients to determine specific genetic mutations associated with breast cancer in the minority population from South Los Angeles, United States. Whole-exome sequencing was performed on DNA extracted from breast cancer tumor biopsies collected from 13 African-American and 15 Hispanic women and 8 matched-normal samples for each ethnic category. The results were analyzed using Ensemble Variant Effect Predictor and Mutation Significance. Additionally, a comparative analysis with The Cancer Genome Atlas data was provided. Our data revealed somatic mutations in genes such as SET domain containing (lysine methyltransferase) 8, serine protease 1 and AT-rich interaction domain 1B (ARID1B) and known breast cancer genes, such as BRCA1/2, TP53 and the DNA damage response genes across all ethnicities. Additionally, Hispanic patients had BRCA1 associated RING domain 1B (BARD1) variants, while African-American patients had higher numbers of nonsynonymous variants in the RAD51 paralog B (RAD51B), ARID1B and X-ray repair cross complementing 3 (XRCC3) genes. In addition, our patients exhibited mutational signature enrichment that indicated DNA homologous recombination repair deficiencies. Therefore, African-American and Hispanic breast cancer samples showed considerable overlap in breast cancer genetic mutations. However, there are differences in specific genetic variants in TP53, BRCA1/2, BARD1 or ARID1B, which will require further study of their role in tumorigenesis.

CircRAD54L2 promotes triple-negative breast cancer progression by regulating the miR-888 family/PDK1 axis.

BACKGROUND: The long-term prognosis of breast cancer with metastasis remains extremely poor. Genetic alterations in tumor cells result in cellular heterogeneity, promoting cancer cells invasion and colonization in some organs during the metastatic process. CircRNAs are very promising as critical biological markers and precise diagnoses in identifying disease mechanisms and developing new methods for effective treatment. However, the role of aberrant expression of circRNAs in breast cancer progression remains largely unknown. METHODS: RNase R treatment and quantitative RT-PCR (qRT-PCR) were performed for circRNA detection. Transwell chamber assays were used to examine the chemotactic migration and invasion of breast cancer cells. RESULTS: This study identified and characterized the circRAD54L2 originating from exon 1, 2, 3, and 4 of the RAD54L2 gene. Importantly, we found that circRAD54L2, rather than RAD54L2 linear mRNA, was significantly upregulated in breast cancer cell lines. Furthermore, we found that inhibiting circRAD54L2 expression markedly reduced the invasion, metastasis, and proliferation of breast cancer cells via sponging of the miR-888 family, which downregulated the expression of pyruvate dehydrogenase kinase 1 (PDK1). CONCLUSION: Our results showed that circRAD54L2 could regulate PDK1 expression by sponging the miR-888 family competing for the ceRNA mechanism, indicating that circRAD54L2 may act as an essential upstream regulator and providing further mechanistic evidence to support the notion that circRAD54L2/miR-888s/PDK1 is a promising therapeutic target in the treatment of breast cancer.

Correction: Dutta et al. Transcriptional Regulation of CCL2 by PARP1 Is a Driver for Invasiveness in Breast Cancer. Cancers 2020, 12, 1317.

In the original publication, there was a mistake in Figure 5D as published [...].

Squalamines in Blockade of Tumor-Associated Angiogenesis and Cancer Progression.

Mechanisms of action of squalamine in human vascular endothelial cells indicate that this compound attaches to cell membranes, potentially interacting with calmodulin, Na+/H+ exchanger isoform NHE3 and other signaling pathways involved in the angiogenic process. Thus, squalamine elicits blockade of VEGF-induced endothelial tube-like formation in vitro. Further, squalamine reduces growth of several preclinical models of human cancers in vivo and acts to stop metastatic tumor spread, actions due largely to blockade of angiogenesis induced by the tumor and tumor microenvironment. Squalamine in Phase I/II trials, alone or combined with standard care, shows promising antitumor activity with limited side-effects in patients with advanced solid cancers. Increased attention on squalamine regulation of signaling pathways with or without combination treatments in solid malignancies deserves further study.

Phytochemicals in Inhibition of Prostate Cancer: Evidence from Molecular Mechanisms Studies.

Prostate cancer is one of the leading causes of death for men worldwide. The development of resistance, toxicity, and side effects of conventional therapies have made prostate cancer treatment become more intensive and aggressive. Many phytochemicals isolated from plants have shown to be tumor cytotoxic. In vitro laboratory studies have revealed that natural compounds can affect cancer cell proliferation by modulating many crucial cellular signaling pathways frequently dysregulated in prostate cancer. A multitude of natural compounds have been found to induce cell cycle arrest, promote apoptosis, inhibit cancer cell growth, and suppress angiogenesis. In addition, combinatorial use of natural compounds with hormone and/or chemotherapeutic drugs seems to be a promising strategy to enhance the therapeutic effect in a less toxic manner, as suggested by pre-clinical studies. In this context, we systematically reviewed the currently available literature of naturally occurring compounds isolated from vegetables, fruits, teas, and herbs, with their relevant mechanisms of action in prostate cancer. As there is increasing data on how phytochemicals interfere with diverse molecular pathways in prostate cancer, this review discusses and emphasizes the implicated molecular pathways of cell proliferation, cell cycle control, apoptosis, and autophagy as important processes that control tumor angiogenesis, invasion, and metastasis. In conclusion, the elucidation of the natural compounds' chemical structure-based anti-cancer mechanisms will facilitate drug development and the optimization of drug combinations. Phytochemicals, as anti-cancer agents in the treatment of prostate cancer, can have significant health benefits for humans.

Diaporine Potentiates the Anticancer Effects of Oxaliplatin and Doxorubicin on Liver Cancer Cells.

Recent studies have shown that diaporine, a novel fungal metabolic product, has a strong in vitro and in vivo anticancer effect on human non-small-cell lung and breast cancers. In this study, three human hepatocarcinoma cell lines (HepG2, Hep3B, and Huh7) were used to evaluate the efficacy of diaporine alone and in combination with the standard cytotoxic drugs oxaliplatin and doxorubicin for the treatment of liver cancer. We demonstrated that diaporine, oxaliplatin, and doxorubicin triggered a concentration- and time-dependent decrease in the number of HepG2 cells. Diaporine at a concentration of 2.5 µM showed almost 100% inhibition of cell counts at 72 h. Similar effects were observed only with much higher concentrations (100 µM) of oxaliplatin or doxorubicin. Decreases in cell numbers after 48 h treatment with diaporine, oxaliplatin, and doxorubicin were also demonstrated in two additional hepatoma cell lines, Hep3B and Huh7. The combination of these drugs at low concentration for 48 h in vitro noticeably showed that diaporine improved the inhibitory effect on the number of cancer cells induced by oxaliplatin or doxorubicin. Additionally, this combination effectively inhibited colony growth in vitro. We found that inhibition of phosphorylation of ERK1/2 significantly increased when diaporine was used in combination with other agents. In addition, we also found that when diaporine was used in combination with doxorubicin or oxaliplatin, their proapoptotic effect greatly increased. We further revealed that the induction of apoptosis in hepatoma cells after treatment is due, at least in part, to the inhibition of phosphorylation of AKT, leading to the activation of caspase-3, inactivation of poly (ADP-ribose) polymerase (PARP), and subsequently to DNA damage, as indicated by the increased level of H2AX. Based on these findings, we suggest that diaporine in combination with the standard cytotoxic drugs oxaliplatin and doxorubicin may play a role in the treatment of liver cancer.

Tumor-Derived Exosomes in Tumor-Induced Immune Suppression.

Exosomes are a class of small membrane-bound extracellular vesicles released by almost all cell types and present in all body fluids. Based on the studies of exosome content and their interactions with recipient cells, exosomes are now thought to mediate "targeted" information transfer. Tumor-derived exosomes (TEX) carry a cargo of molecules different from that of normal cell-derived exosomes. TEX functions to mediate distinct biological effects such as receptor discharge and intercellular cross-talk. The immune system defenses, which may initially restrict tumor progression, are progressively blunted by the broad array of TEX molecules that activate suppressive pathways in different immune cells. Herein, we provide a review of the latest research progress on TEX in the context of tumor-mediated immune suppression and discuss the potential as well as challenges of TEX as a target of immunotherapy.

Roles of Protein Disulfide Isomerase in Breast Cancer.

Protein disulfide isomerase (PDI) is the endoplasmic reticulum (ER)'s most abundant and essential enzyme and serves as the primary catalyst for protein folding. Due to its apparent role in supporting the rapid proliferation of cancer cells, the selective blockade of PDI results in apoptosis through sustained activation of UPR pathways. The functions of PDI, especially in cancers, have been extensively studied over a decade, and recent research has explored the use of PDI inhibitors in the treatment of cancers but with focus areas of other cancers, such as brain or ovarian cancer. In this review, we discuss the roles of PDI members in breast cancer and PDI inhibitors used in breast cancer research. Additionally, a few PDI members may be suggested as potential molecular targets for highly metastatic breast cancers, such as TNBC, that require more attention in future research.

Elevated Baseline Serum PD-L1 Level May Predict Poor Outcomes from Breast Cancer in African-American and Hispanic Women.

BACKGROUND: The therapeutic targeting of PD-1/PD-L1 has shown clinical efficacy in treating metastatic breast cancer. We investigated the clinical significance of measuring serum PD-L1 levels in African-American and Hispanic women with breast cancer. METHODS: PD-L1 levels were measured with the ELISA method from the serum samples of 244 African-Americans and Hispanics with breast cancer and 155 women without cancers. The levels of INFα2 and TNFα were measured with a Luminex multiplex assay. The protein levels of pAkt and CD44/CD24 in tumor cells were tested with immunohistochemistry analysis. Cox regression was used to assess the predicting role of serum PD-L1 for disease-free survival (DFS). RESULTS: PD-L1 levels were significantly elevated in breast cancer cases compared to non-cancer cases. The high PD-L1 levels were associated with HER2-positive and triple-negative breast cancer. PD-L1 level independently predicted DFS in both African-American and Hispanic women. The evaluated PD-L1 level was found to be associated with high IFNα2 and TNFα in breast cancer patients. CONCLUSIONS: PD-L1 serum levels can predict DFS in African American and Hispanic women with breast cancer. Furthermore, a high level of PD-L1 is more likely to be associated with tumor loss PTEN and the activation of Akt or with breast cancer cells expressing CD44high/CD24low. Further validation studies are needed to determine if PD-L1 could serve as a biomarker for patient selection for anti-PD-L1 therapy and assess treatment outcomes.