Pathophysiology Of Breast Cancer Research Articles

Quantitative assessment of background parenchymal enhancement is associated with lifetime breast cancer risk in screening MRI.

To compare the quantitative background parenchymal enhancement (BPE) in women with different lifetime risks and BRCA mutation status of breast cancer using screening MRI. This study included screening MRI of 535 women divided into three groups based on lifetime risk: nonhigh-risk women, high-risk women without BRCA mutation, and BRCA1/2 mutation carriers. Six quantitative BPE measurements, including percent enhancement (PE) and signal enhancement ratio (SER), were calculated on DCE-MRI after segmentation of the whole breast and fibroglandular tissue (FGT). The associations between lifetime risk factors and BPE were analyzed via linear regression analysis. We adjusted for risk factors influencing BPE using propensity score matching (PSM) and compared the BPE between different groups. A two-sided Mann-Whitney U-test was used to compare the BPE with a threshold of 0.1 for multiple testing issue-adjusted p values. Age, BMI, menopausal status, and FGT level were significantly correlated with quantitative BPE based on the univariate and multivariable linear regression analyses. After adjusting for age, BMI, menopausal status, hormonal treatment history, and FGT level using PSM, significant differences were observed between high-risk non-BRCA and BRCA groups in PEFGT (11.5 vs. 8.0%, adjusted p = 0.018) and SERFGT (7.2 vs. 9.3%, adjusted p = 0.066). Quantitative BPE varies in women with different lifetime breast cancer risks and BRCA mutation status. These differences may be due to the influence of multiple lifetime risk factors. Quantitative BPE differences remained between groups with and without BRCA mutations after adjusting for known risk factors associated with BPE. BRCA germline mutations may be associated with quantitative background parenchymal enhancement, excluding the effects of known confounding factors. This finding can provide potential insights into the cancer pathophysiological mechanisms behind lifetime risk models. Expanding understanding of breast cancer pathophysiology allows for improved risk stratification and optimized screening protocols. Quantitative BPE is significantly associated with lifetime risk factors and differs between BRCA mutation carriers and noncarriers. This research offers a possible understanding of the physiological mechanisms underlying quantitative BPE and BRCA germline mutations.

Abstract 4775: Unveiling caveolin-1's crucial role in breast cancer progression and metastasis: A molecular perspective

Abstract Background: Breast cancer, particularly its metastatic form, constitutes a significant portion of oncological mortality. Caveolin-1 (Cav-1), a caveolae structural protein, has been implicated in cellular processes such as proliferation, apoptosis, autophagy, and cellular motility (aberrant in breast cancer). With its dual role as a tumor suppressor and promoter, Cav-1's function in breast cancer pathophysiology requires elucidation for potential therapeutic targeting. Methods: We utilized a syngeneic mouse model to engineer Cav-1 deficient 4T1 murine mammary carcinoma cells which mirror the characteristics of stage IV breast cancer to investigate Cav-1's role in tumor growth and metastasis. We assessed cellular proliferation and lung metastasis, compared with wild-type controls, and performed molecular analyses to evaluate epithelial and mesenchymal marker expression, stemness-related markers, and autophagy-related gene expression. Results: Cav-1 ablation corresponded with a marked decrease in tumor proliferation and lung metastasis, indicating a suppressive role in tumor progression. Molecular characterization revealed downregulated epithelial markers (E-cadherin, β-catenin), transcription factors (TWIST1/2), and stem cell markers (NANOG, OCT4, SOX2, c-MYC, SALL4), with concurrent upregulation of the mesenchymal marker vimentin. Enhanced expression of autophagy-related genes (Beclin-1, ATG5, ATG16) was also observed, suggesting a disruption in autophagic pathways. Conclusion: Our findings underscore the critical role of Cav-1 in breast cancer progression, specifically its function in suppressing metastasis and modulating cellular phenotypes. Targeting Cav-1 could represent a novel therapeutic strategy to mitigate breast cancer growth and dissemination. Further research is warranted to explore the therapeutic potential of modulating Cav-1 in breast cancer treatment. Citation Format: Rizwana Begum, Shilpa Thota, Dhirendra Pratap Singh, Naveen Chintala, Abhishek Pandit, Biplov Sapkota, Joseph Francis. Unveiling caveolin-1's crucial role in breast cancer progression and metastasis: A molecular perspective [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4775.

Adipose Tissue in Breast Cancer Microphysiological Models to Capture Human Diversity in Preclinical Models.

Female breast cancer accounts for 15.2% of all new cancer cases in the United States, with a continuing increase in incidence despite efforts to discover new targeted therapies. With an approximate failure rate of 85% for therapies in the early phases of clinical trials, there is a need for more translatable, new preclinical in vitro models that include cellular heterogeneity, extracellular matrix, and human-derived biomaterials. Specifically, adipose tissue and its resident cell populations have been identified as necessary attributes for current preclinical models. Adipose-derived stromal/stem cells (ASCs) and mature adipocytes are a normal part of the breast tissue composition and not only contribute to normal breast physiology but also play a significant role in breast cancer pathophysiology. Given the recognized pro-tumorigenic role of adipocytes in tumor progression, there remains a need to enhance the complexity of current models and account for the contribution of the components that exist within the adipose stromal environment to breast tumorigenesis. This review article captures the current landscape of preclinical breast cancer models with a focus on breast cancer microphysiological system (MPS) models and their counterpart patient-derived xenograft (PDX) models to capture patient diversity as they relate to adipose tissue.

CORRELATION BETWEEN FEMALE JUNIOR HIGH SCHOOL STUDENTS KNOWLEDGE AND BREAST SELF EXAMINATION BEHAVIOR

Background : Breast cancer is a painless lump, can develop and invade surrounding breast tissue then spread to nearby lymph nodes or to other organs in the body. The high mortality rate of breast cancer is due to a lack of knowledge about breast cancer and early detection so that it comes to health services at late stage. As recommended by the government, the most effective screening method is Breast Self Examination which is very easy but many teenagers do not know this method. The aim of this study is to know correlation between students knowledge and Breast Self Examination Behavior. Method : Descriptive quantitative reasearch through a cross sectional approach. Population in this study were 218 female students at Ananda Junior High School Bekasi City West Java in 2022 with 141 students for sample using simple random sampling technique. Research instruments using questionnaires about knowledge of pathophysiology and breast cancer prevention as independent variable and Breast Self Examination behavior as a dependent variable using the chi square statistical test. Results : Majority as many 91.5% of Ananda Junior High School students had never done Breast Self Examination, had poor knowledge about the pathophysiology of breast cancer (93.6%) and breast cancer prevention (83.7%). Then obtained a p value of 0.000 (p < 0.05) which means that there is a significant correlation between knowledge about the pathophysiology and breast cancer prevention with Breast Self Examination behavior. Conclusion : The proportion of Breast Self Examination behaviour of Ananda Bekasi junior high school students is very low (8.5%). Most respondents had less knowledge about the pathophysiology of breast cancer (93.6%) and breast cancer prevention (83.7%). Suggestions: Conduct ongoing research to see any changes in respondent behavior in the future.

Breast cancer malignancy is governed by regulation of the macroH2A2/TM4SF1 axis, the AKT/NF-κB pathway, and elevated MMP13 expression.

The histone variant, macroH2A (mH2A) influences gene expression through epigenetic regulation. Tumor suppressive function of mH2A isoforms has been reported in various cancer types, but few studies have investigated the functional role of mH2A2 in breast cancer pathophysiology. This study aimed to determine the significance of mH2A2 in breast cancer development and progression by exploring its downstream regulatory mechanisms. Knockdown of mH2A2 facilitated the migration and invasion of breast cancer cells, whereas its overexpression exhibited the opposite effect. In vivo experiments revealed that augmenting mH2A2 expression reduced tumor growth and lung metastasis. Microarray analysis showed that TM4SF1 emerged as a likely target linked to mH2A2 owing to its significant suppression in breast cancer cell lines where mH2A2 was overexpressed among the genes that exhibited over twofold upregulation upon mH2A2 knockdown. Suppressing TM4SF1 reduced the migration, invasion, tumor growth, and metastasis of breast cancer cells in vitro and in vivo. TM4SF1 depletion reversed the increased aggressiveness triggered by mH2A2 knockdown, suggesting a close interplay between mH2A2 and TM4SF1. Our findings also highlight the role of the mH2A2/TM4SF1 axis in activating the AKT/NF-κB pathway. Consequently, activated NF-κB signaling leads to increased expression and secretion of MMP13, a potent promoter of metastasis. In summary, we propose that the orchestrated regulation of the mH2A2/TM4SF1 axis in conjunction with the AKT/NF-κB pathway and the subsequent elevation in MMP13 expression constitute pivotal factors governing the malignancy of breast cancer.

Renal insufficiency in breast cancer patients; a review study

The latest statistics and estimations indicated that breast cancer occurs in one-fourth of women worldwide and is responsible for one in six cancer deaths among women. A bilateral relationship seems to exist between breast cancer pathophysiology and kidney failure. Consideration should be given to this relationship when selecting a treatment protocol. This paper reviews the association between these two factors in breast cancer patients. There are many aspects to consider in the association between breast cancer and renal insufficiency. A breast cancer patient with normal kidney function is at risk of developing kidney failure due to paraneoplastic syndromes, hypercalcemia, and in rare cases, tumor lysis syndrome (TLS). In defining the optimal treatment protocol for each breast cancer patient, clinicians should consider the patient’s basal glomerular filtration rate (GFR). Frequent renal clearance monitoring and taking immediate action at the time GFR begins to decrease will lower the rate of kidney failure in breast cancer patients. Lastly, patients with chronic kidney disease who are recently diagnosed with breast cancer may have higher morbidity and mortality compared to breast cancer patients with normal GFR. Further investigation is needed to lower morbidity and mortality in such patients.

Long Noncoding RNAs-LET Behave as a Noncoding Signature for Early-Onset Menarche and Late-Onset Menopause in Breast Cancer Patients

Background: Breast cancer (BC) as a major cause of cancer-related death in women shows a very complex molecular and clinical phenotype, which has reduced the effectiveness of medical interventions. Evidence suggests that long noncoding RNAs (lncRNAs) are responsible for an important part of this complexity. This study aims to assess the expression and clinical implication of lncRNA LET in the pathobiology of BC. Materials and Methods: Quantitative real-time polymerase chain reaction was used to measure the expression of lncRNA-LET in breast tumors and adjacent normal-appearing tissues from 4 BC patients, as well as normal mammary tissues. Moreover, a bioinformatics approach was applied to uncover the potential lncRNA-LET-mediated sponge regulatory network as LET/miRNA/mRNA crosstalk. Results: Our study revealed that lncRNA-LET was significantly down-expressed not only in breast tumors but also in normal appearing breast tissues samples from BC subjects compared with true normal breast tissues obtained from healthy women. The low level of lncRNA-LET was meaningfully associated with early-onset menarche (≤13 years) and late-onset menopause (≥50) in patients. Moreover, the bioinformatics analyses support that lncRNA-LET could function as a tumor suppressor miRNA sponge. Conclusion: The results indicate that normal appearing breast tissues can undergo tumor-related molecular changes. Furthermore, they reveal the potential role of the dysregulation in LET-mediated ceRNA network in the pathophysiology of BC.

The mechanism of lapatinib and its application in breast cancer

This paper aims to study the synthetic route, mechanism of action and application of lapatinib in breast cancer. As a common malignant tumor, breast cancer poses a serious threat to the life and health of patients. As an effective targeted drug, lapatinib is significant in treating breast cancer. Its pharmacological effects can block the growth and metastasis of tumor cells by inhibiting specific signaling pathways and affect cancer cells metabolism and drug efficacy. Its molecular mechanism is mainly through targeting the epidermal growth factor receptor (EGFR) to inhibit the proliferation and survival of tumor cells. Studies on lapatinibs drug metabolism and pharmacodynamics also described its metabolism and therapeutic effect in vivo. Secondly, the pathophysiology of breast cancer was summarized, including the pathogenesis, clinical manifestations, and molecular biological characteristics of breast cancer. The therapeutic effect, application, efficacy evaluation, and adverse reaction management of lapatinib were analyzed for the application of lapatinib in the treatment of breast cancer. Moreover, the existing lapatinib synthetic routes were described. Lapatinib has a substantial treatment influence and may effectively decrease harmful reactions when used to treat breast cancer. Nevertheless, additional study is required to ascertain its optimal application and possible mechanism of action in breast cancer treatment.

Dulaglutide as a demethylating agent to improve the outcome of breast cancer.

Background: Dulaglutide emerged as a promising therapeutic option for diabetes mellitusType 2 (DM2). Aims: Owingto epigenetic similarities between the pathophysiology of DM2 and breast cancer (BC), we investigated the antitumor effect of dulaglutide. Materials & methods: To investigate the effect of dulaglutide, we analyzed the expression of methylated gene promoter regions in BC (ESR1, CDH1 and ADAM33). Results: Dulaglutide increased the expression of ESR1, CDH1 and ADAM33 up to fourfold in the MDA-MB-231 lineage by demethylating the gene promoter regions. This effect was translated to in vivo antitumoral activity and revealed significant tumor inhibition by combining the half-dose of methotrexate with dulaglutide. Conclusion: This therapy may mitigate the severe side effects commonly associated with chemotherapy.

Structure-based virtual screening, molecular simulation and free energy calculations of traditional Chinese medicine, ZINC database revealed potent inhibitors of estrogen-receptor α (ERα)

Breast Cancer, a heterogeneous disease at the molecular level, is the most common cause of woman mortality worldwide. We used molecular screening and simulation approaches to target nuclear receptor protein-estrogen receptor alpha (Erα) protein to design and develop of specific and compelling drugs from traditional Chinese medicine (TCM), and ZINC database against pathophysiology of breast cancer. Using virtual screening, only six hits TCM22717, TCM23524, TCM31953, while ZINC05632920, ZINC05773243, and ZINC12780336 demonstrated better pharmacological potential than the 4-hydroxytamoxifen (OHT) taken as control. Binding mode of each of the top hit revealed that these compounds could block the main active site residues and block the function of Erα protein. Moreover, molecular simulation revealed that the identified compounds exhibit stable dynamics and may induce stronger therapeutic effects in experimental setup. All the complexes reported tighter structural packing and less flexible behaviour. We found that the average hydrogen bonds in the identified complexes remained higher than the control drug. Finally, the total binding free energy demonstrated the best hits among the all. The BF energy results revealed −30.4525 ± 3.3565 for the 4-hydroxytamoxifen (OHT)/Erα complex, for the TCM22717/Erα −57.0597 ± 3.4852 kcal/mol, for the TCM23524/Erα complex the BF energy was −56.9084 ± 3.3737 kcal/mol, for the TCM31953/Erα the BF energy was −32.4191 ± 3.8864 kcal/mol while for the ZINC05632920/Erα complex −46.3182 ± 2.7380, ZINC05773243/Erα complex −38.3690 ± 2.8240, and ZINC12780336/Erα complex the BF energy was calculated to be −35.8048 ± 4.1571 kcal/mol. Communicated by Ramaswamy H. Sarma

OR05-01 Myeloid Cell Intrinsic NR0B2 Inhibits Regulatory T Cell Expansion Within The Tumor Microenvironment: Potential Novel Strategy For Breast Cancer Immunotherapy

Abstract Disclosure: H. Vidana Gamage: None. S. Shahoei: None. S. Albright: None. T. Nguyen: None. R. Farmer: None. E. Weisser: None. R. Bautista Rivas: None. C.P. Schane: None. Y. Wang: None. A. Nelczyk: None. L. Ma: None. S. Tiwari: None. A. Das Gupta: None. S. Bendre: None. L. Apetoh: None. P. Hergenrother: None. E.R. Nelson: None. Breast cancer remains the second leading cause of cancer-related death in women. Immune-oncology interventions for the treatment of breast cancer have thus far been underwhelming, providing strong rationale for the development of drugs to increase their efficacy. A major obstacle to immunotherapy is the highly immunosuppressive tumor microenvironment. This phenomenon is strongly maintained by myeloid cells and regulatory T cells (Tregs), which are associated with immune escape, poor prognosis and treatment resistance. Importantly, myeloid cells are also critical for a robust anti-tumor response. Therefore, we require strategies to re-educate myeloid cells rather than eliminating them. Elevated cholesterol is a risk factor for breast cancer, while cholesterol-lowering drugs are associated with a good prognosis. Previous work has demonstrated that certain downstream metabolites of cholesterol, can promote immune escape and metastatic progression. The nuclear receptor NR0B2 is a critical negative regulator of cholesterol homeostasis. Mining clinical data, we have found that high tumoral expression of NR0B2 is associated with an increased time to recurrence. Single cell RNA-sequencing indicates that NR0B2 is expressed within the myeloid cells of normal breast tissue. Thus, we hypothesized that myeloid cell NR0B2 is involved in breast cancer pathophysiology and can be used as a druggable target. Intriguingly, overexpression of NR0B2 or activation with a small molecule agonist in murine bone marrow derived macrophages (BMDMs) or dendritic cells skewed T cell expansion away from Tregs. Conversely, Treg expansion increased when NR0B2 was knocked down. In order to investigate the role of NR0B2 in vivo, we monitored the growth of tumors grafted into mice that had NR0B2 genetically knocked out in the myeloid lineage (NR0B2fl/fl;LysMCre+) and respective control mice (NR0B2wt/wt;LysMCre+). Mice lacking NR0B2 exhibited significantly increased tumor growth and elevated tumor infiltrating Tregs. Additionally, human breast tumors samples indicated an inverse correlation between NR0B2 and FOXP3 (marker for Tregs). We further investigated the downstream targets of NR0B2 mediating this anti-tumor phenotype and identified that NLRP3 inflammasome-IL1β axis is a likely modulator in re-educating myeloid cell-Treg function. Importantly, a putative small molecule agonist decreased established metastatic lesions and increased the efficacy of αPD-L1 therapy. Subsequent medicinal chemistry was used to develop a novel NR0B2 agonist with strong anti-metastatic properties when used as a single agent in a preclinical mouse model. Collectively, our data implicates NR0B2 within myeloid cells as a modulator of Tregs, a cell population that has thus far been therapeutically intractable. Therefore, NR0B2 may prove to be a promising therapeutic strategy to improve breast cancer immunotherapy. Presentation: Thursday, June 15, 2023

The expression of matrix metalloproteinase 2, 9 and 11 in Ethiopian breast cancer patients

IntroductionMatrix metalloproteinases (MMPs) play a pathophysiological role in cancer initiation and progression. Numerous studies have examined an association between MMP-2, MMP-9, and MMP-11 expression and clinicopathological characteristics of breast cancer (BC); however, no research has been done on the MMP expression levels in BC cases from Ethiopia.Materials and methodsA total of 58 formalin-fixed paraffin-embedded breast tissue samples encompassing 16 benign breast tumors and 42 BC were collected. The RNA was extracted and quantitative reverse-transcription PCR was performed. GraphPad Prism version 8.0.0 was used for statistical analysis.ResultsThe MMP-11 expression levels were significantly higher in breast cancer cases than in benign breast tumors (P = 0.012). Additionally, BC cases with positive lymph nodes and ER-positive receptors had higher MMP-11, MMP-9, and MMP-2 expression than cases with negative lymph nodes and ER-negative, respectively. The MMP-11 and MMP-9 expressions were higher in grade III and luminal A-like tumors than in grade I-II and other subtypes, respectively.ConclusionThe MMP-11 expression was higher in BC than in benign breast tumors. Additionally, MMP-11, MMP-9, and MMP-2 were higher in BC with positive lymph nodes and estrogen receptors. Our findings suggest an important impact of MMPs in BC pathophysiology, particularly MMP-11.

A comprehensive review on Ellagic acid in breast cancer treatment: From cellular effects to molecular mechanisms of action.

Globally, breast cancer (BC) is the leading cause of cancer-related deaths in women. Hence, developing a therapeutic plan to overcome the disease is crucial. Numerous factors such as endogenous hormones and environmental factors may play a role in the pathophysiology of BC. Regarding the multi-modality treatment of BC, natural compounds like ellagic acid (EA) received has received increased interest in antitumor efficacy with lower adverse effects. Based on the results of this comprehensive review, EA has multiple effects on BC cells including (1) suppresses the growth of BC cells by arresting the cell cycle in the G0/G1 phase, (2) suppresses migration, invasion, and metastatic, (3) stimulates apoptosis in MCF-7 cells via TGF-β/Smad3 signaling axis, (4) inhibits CDK6 that is important in cell cycle regulation, (5) binds to ACTN4 and induces its degradation via the ubiquitin-proteasome pathway, inducing decreased cell motility and invasion in BC cells, (6) inhibits the PI3K/AKT pathway, and (7) inhibits angiogenesis-associated activities including proliferation (reduces VEGFR-2 tyrosine kinase activity). In conclusion, EA exhibits anticancer activity through various molecular mechanisms that influence key cellular processes like apoptosis, cell cycle, angiogenesis, and metastasis in BC. However, further researches are essential to fully elucidate its molecular targets and implications for clinical applications.

Increased Expression of miR-223-3p and miR-375-3p and Anti-Inflammatory Activity in HDL of Newly Diagnosed Women in Advanced Stages of Breast Cancer.

The expression of inflammation-related miRs bound to high-density lipoproteins (HDLs), the anti-inflammatory activity of HDLs isolated from individuals with breast cancer, and controls were determined. Forty newly diagnosed women with breast cancer naïve of treatment and 10 control participants were included. Cholesterol-loaded bone-marrow-derived macrophages were incubated with HDL from both groups and challenged with lipopolysaccharide (LPS). Interleukin 6 (IL6) and tumor necrosis factor (TNF) in the medium were quantified. The miRs in HDLs were determined by RT-qPCR. Age, body mass index, menopausal status, plasma lipids, and HDL composition were similar between groups. The ability of HDL to inhibit IL6 and TNF production was higher in breast cancer compared to controls, especially in advanced stages of the disease. The miR-223-3p and 375-3p were higher in the HDLs of breast cancer independent of the histological type of the tumor and had a high discriminatory power between breast cancer and controls. The miR-375-3p was greater in the advanced stages of the disease and was inversely correlated with the secretion of inflammatory cytokines. Inflammation-related miRs and the anti-inflammatory role of HDLs may have a significant impact on breast cancer pathophysiology.

Abstract P3-05-13: INFLUENCE OF METABOLIC SYNDROME ON OVERALL SURVIVAL (OS), DISEASE FREE SURVIVAL (DFS) AND INVASIVE FREE SURVIVAL (IFV) IN A COHORT OF PATIENTS TREATED FOR BREAST CANCER IN BRAZIL

Abstract Introduction: Metabolic syndrome can be defined as a set of conditions - central obesity (waist circumference), elevated blood pressure, reduced HDL cholesterol, increased triglycerides and glucose intolerance - which is known to be associated with a higher risk in the development of cardiovascular disease and type 2 diabetes. It affects approximately 30% of the population of women over 50 years of age. In view of the risk factors described above, it is important to seek, in addition to the screening recommended by the Ministry of Health (a mammogram every two years in women aged 50 to 69 years), ways to reduce the risk of breast cancer with regard to to behavioral factors. Practicing the maintenance of adequate weight and physical activities can contribute to the reduction of this pathology. Therefore, even in the pathophysiology of breast cancer, its relationship with the metabolic syndrome is seen, which is often the cause - and even consequence - women treated for breast cancer seem to have an additional risk of metabolic syndrome, resulting from excess adiposity. and effect of treatments. Objectives: To evaluate the relationship between metabolic syndrome at the diagnosis of breast cancer and overall survival, disease-free survival and invasive disease-free survival. Methodology: Retrospective longitudinal observational study of the cohort type carried out in the Mastology sector of the Gynecology and Obstetrics Service of the Hospital do Servidor Público Estadual de São Paulo “Francisco Morato Oliveira. We evaluated the rates of local recurrence, distant metastases and overall survival of patients with malignant breast cancer in each group. Results: From January 2017 to December 2020, 375 patients underwent surgical treatment for breast cancer at the Hospital do Servidor Público Estadual, of which 25 were excluded due to loss of follow-up, 10 due to incomplete data and 5 due to diagnosis of metastases. Thus, 335 patients were eligible for the study, with a mean age of 63.4 ± 1.4 years, and a mean follow-up time of 48 ± 1.4 years. Metabolic syndrome (MS) is present in 109 (32 .5%) patients, while 226 (67.5%) do not have MS. Regarding the characteristics of prognostic factors, that is, KI 67, molecular classification and staging, in table 3 we can observe that patients with metabolic syndrome have a very similar distribution, while those without MS have a KI 67 ≥ 14% in 62.4% of the patients. patients with a significant difference. The molecular profile in MS patients is 39.4% Luminal A patients and 42.5% Luminal B patients without MS, with a significant difference in distribution. Regarding clinical staging, patients with MS have initial clinical stage I and IIA in 54.1%, and advanced stage IIB 20.2% III 25.7%, while patients without MS have initial clinical stage 65%, advanced stage IIB 11.1%m III 23.9, results with a significant difference. When we evaluated the presence of obesity as a factor of worsening of prognostic factors, we did not find significant differences. We evaluated the temporal outcomes of overall survival, disease-free survival, and invasive disease-free survival. The overall sample survival was 37.3 years with a CI 1.1 years, disease-free survival was 35.9 years with a CI 1.2 years, and invasive disease-free survival was 36.9 years with CI 1,3 years. When we compared these outcomes with the presence of MS, we observed a significant difference in all outcomes. Conclusions: The presence of MS at diagnosis does not worsen overall survival, disease-free survival or invasive disease-free survival. Overall Survival (OS) for Breast Cancer and Metabolic Syndrome Overall Survival (OS) for Breast Cancer and Metabolic Syndrome Disease Free Survival (DFS) for Breast Cancer and Metabolic Syndrome Disease Free Survival (DFS) for Breast Cancer and Metabolic Syndrome Invasive Free Survival (IFS) for Breast Cancer and Metabolic Syndrome Invasive Free Survival (IFS) for Breast Cancer and Metabolic Syndrome Citation Format: MARCELO ANTONINI, AMANDA LEAL GUIMARAES, FERNANDA GRACE BAUk RICHTER, ODAIR FERRARO, REGINALDO G. COELHO LOPES, JULIANA M. REAL, ANDRE MATTAR. INFLUENCE OF METABOLIC SYNDROME ON OVERALL SURVIVAL (OS), DISEASE FREE SURVIVAL (DFS) AND INVASIVE FREE SURVIVAL (IFV) IN A COHORT OF PATIENTS TREATED FOR BREAST CANCER IN BRAZIL [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-05-13.

Abstract P1-05-34: MicroRNAs as Prognostic Markers in Breast Cancer

Abstract Background: Breast cancer (BC) is the most common cancer and the second leading cause of cancer death in American women. BC disproportionally affects women of ethnic minorities, especially Black and Hispanic. While this disparity has been acknowledged and social determinations of health remains an important contributor, BC pathophysiology is yet to be elucidated in minorities. MicroRNAs (miRNA), including but not limited to let-7, 125-3p, 192-5p, 451a, play regulatory roles in cancer pathobiology and progression in many cancer types, including but not limited to BC. In our lab, in vitro and in vivo studies on mouse models demonstrated that miR-23b and miR-27b had crucial roles in cancer progression in BC via mechanisms that involves nischarin, an integrin-binding protein, and were associated with worse outcome. Moreover, miRNAs can be detected and are stable in blood samples, and thus the detection has a profound clinical impact on diagnosis. Study Design: Between April 2021 and May 2022, 30 newly diagnosed patients with BC and 30 patients without any cancer diagnosis at University Medical Center- New Orleans were enrolled on the study (IRB# 936). 86% of patients are African American or Hispanics. Plasma samples were collected before any medical intervention for BC. Plasma miRNAs were isolated and miRNA expression were performed utilizing RT-PCR. Results: Expressions of let-7 and 125a miRNAs are two times higher in plasma of patients with BC compared to patients without a diagnosis of cancer. There was no difference in miRNA expression in circulatory 23b, 27b, 192-5p, and 451a. Among breast cancer types, there are two-fold decreased expression of 192-5p and 451a in triple negative compared to hormone positive BC. Conclusion: This project will add to the body of knowledge on roles of miRNAs as prognostic markers in patients with BC, more importantly, triple negative BC, and elucidate pathophysiologic mechanism contributing to racial disparity in breast cancer treatment and recurrence. In the near future, we aim to examine effects of chemotherapy and surgery on the expression of circulatory microRNAs. Citation Format: Anh Q. Nguyen, Colin Cunningham, Samuel Okpechi, Hassan Yousefi, Shawn McKinney, Brian Boulmay, Agustin Garcia, Suresh Alahari. MicroRNAs as Prognostic Markers in Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-05-34.

Discovery of differentially expressed novel miRNAs in breast normal cells and their putative targets.

MicroRNAs (miRNAs) play critical role in normal breast development and their altered expression may lead to breast cancer. Identification of new miRNAs allows us to understand the normal physiological process and associated disease pathophysiology. In the present study we identify the novel miRNAs in withaferin A treated breast normal cells (MCF-10A) using small RNA sequencing. The pathophysiological potential of the identified miRNAs was checked by studying their expression pattern in MDA-MB-231 and MCF-7 breast cancer cells using qRT-PCR technique. The secondary/tertiary structure of the identified miRNAs, target gene enrichment in Gene Ontology terms and KEGG pathway, miRNA-mRNA interaction of the sorted target genes, miRNA-mRNA/miRNA-argonaute protein/miRNA-mRNA-argonaute protein interaction and stability, were studied using bioinformatics tools/software, and molecular dynamics simulations. Hsa-miR-N88585 and hsa-miR-N461089 were identified and validated as novel miRNAs in normal breast cells. Up-expression of identified miRNAs in MDA-MB-231 and MCF-7 cells indicates their oncogenic nature. Identified target genes were enriched in classical signaling pathways (AMPK and Ras) and important GO terms. PLXDC2, BHLHE40, ARMC8, and PECAM1, CDC27, KCNK3 genes were sorted as putative targets for hsa-miR-N88585 and hsa-miR-N461089, respectively. MD simulation revealed stable hsa-miR-N88585/hsa-miR-N461089-AGO protein complex formation which indicates their further processing. In conclusion, the study identifies hsa-miR-N88585 and hsa-miR-N461089 as novel miRNAs in breast normal cells which are significantly inversely expressed in breast cancer cells. Further experiments are required to study the role of identified novel miRNAs in normal breast development and pathophysiology of breast cancer.

Dysregulated Cholesterol Metabolism Including Oxysterols in the Pathophysiology of Breast Cancer: Therapeutic Implications - A Narrative Review

Dysregulated Cholesterol Metabolism Including Oxysterols in the Pathophysiology of Breast Cancer: Therapeutic Implications - A Narrative Review

DCXR promotes cell proliferation by promoting the activity of aerobic glycolysis in breast cancer.

The function of human dicarbonyl/L‑xylulose reductase (DCXR) in the pathophysiology of breast cancer is yet to be elucidated. The present study aimed to investigate the function of DCXR in glycolysis and the cell cycle of breast cancer cells with respect to cell proliferation. Differential expressed DCXR was identified in The Cancer Genome Atlas (TCGA) database and verified in clinical breast cancer tissue. DCXR silencing and overexpression were induced by RNA interference and lentiviral vectors, respectively. Cell cycle progression, proliferation and glycolytic activity of breast cancer cells were detected by flow cytometry, Cell Counting Kit‑8 assay and chemical methods, respectively. Tumorigenicity was detected using nude mice xenograft models. The expression of DCXR was increased in TCGA breast cancer database and the function of DCXR was enriched in 'glycolysis' and 'cell cycle'. Further analysis using clinical breast cancer samples confirmed upregulation of DCXR. The silencing of DCXR suppressed proliferation and cell cycle progression of breast cancer cells and significantly decreased the capacity for glycolysis, thereby demonstrating the effect of DCXR on the function of breast cancer cells. Similar conclusions were obtained in DCXR overexpressing cells; notably, DCXR overexpression promoted proliferation, cell cycle progression at S phase and glycolysis. 2‑Deoxy‑D‑glucose inhibited the effect of DCXR on the proliferation and cell cycle progression of breast cancer cells. The present study revealed that DCXR regulated breast cancer cell cycle progression and proliferation by increasing glycolysis activity and thus may serve as an oncogene for breast cancer.

In silico molecular docking approach and in vitro cytotoxic, antioxidant, antimicrobial and anti-inflammatory activity of Ixora brachiata Roxb

The Ixora brachiata Roxb. methanolic leaf extract yielded significant in vitro free radical scavenging activity against DPPH (60% of inhibition obtained in 100 μg/mL) and ABTS (62% of inhibition obtained in 100 μg/mL) radicals, compared to ascorbic acid positive control. The antibacterial activity was modest when compared with antibiotics controls. The extract was effective, especially against Escherichia coli and Staphylococcus aureus, yielding 5 ± 0.9 (mm) and 4 ± 0.5 (mm), respectively, at a 10 mg/mL concentration. MTT assay showed an IC50 value of 51 μg/mL. The plant extract was rich in antioxidants, and anthraquinones were detected. When compared to aspirin (100–800 μg/mL) which had much greater anti-inflammatory (HRBC stabilisation) activity of 45–84%, the methanolic extract of I. brachiata was found to possess 10–45% activity in the same concentration range of 100–800 μg/mL. Since aspirin is a pure compound (and a routinely employed anti-inflammatory standard) and the plant extract contains multiple compounds with differential anti-inflammatory activities, the activity of aspirin may have been much higher. Qualitative and quantitative analyses showed the presence of different classes of primary and secondary metabolites in the leaf extract. The GC-MS (Gas chromatography-mass spectrometry) study in the plant extract showed that ∼22 different volatile compounds were present. The in vitro cytotoxic potential of the extract was assessed in MCF-7 breast cancer cell lines, and the bioactive compounds β-sitosterol, γ-sitosterol, δ-tocopherol and squalene, which were identified through GC-MS, were further assessed for binding to salient receptor proteins which are routinely involved in breast cancer pathophysiology, like PI3K, MMP-9, mTOR and ERβ.