ACSL3 regulates breast cancer progression via lipid metabolism reprogramming and the YES1/YAP axis

Objective:Mitochondrial fatty acid oxidation is a metabolic pathway whose dysregulation is recognized as a critical factor in various cancers,because it sustains cancer cell survival,proliferation,and metastasis.The acyl-Co A synthetase long-chain(ACSL)family is known to activate long-chain fatty acids,yet the specific role of ACSL3 in breast cancer has not been determined.Methods:We assessed the prognostic value of ACSL3 in breast cancer by using data from tumor samples.Gain-of-function and lossof-function assays were also conducted to determine the roles and downstream regulatory mechanisms of ACSL3 in vitro and in vivo.Results:ACSL3 expression was notably downregulated in breast cancer tissues compared with normal tissues,and this phenotype correlated with improved survival outcomes.Functional experiments revealed that ACSL3 knockdown in breast cancer cells promoted cell proliferation,migration,and epithelial±mesenchymal transition.Mechanistically,ACSL3 was found to inhibitβ-oxidation and the formation of associated byproducts,thereby suppressing malignant behavior in breast cancer.Importantly,ACSL3 was found to interact with YES proto-oncogene 1,a member of the Src family of tyrosine kinases,and to suppress its activation through phosphorylation at Tyr419.The decrease in activated YES1 consequently inhibited YAP1 nuclear colocalization and transcriptional complex formation,and the expression of its downstream genes in breast cancer cell nuclei.Conclusions:ACSL3 suppresses breast cancer progression by impeding lipid metabolism reprogramming,and inhibiting malignant behaviors through phospho-YES1 mediated inhibition of YAP1 and its downstream pathways.These findings suggest that ACSL3 may serve as a potential biomarker and target for comprehensive therapeutic strategies for breast cancer.

RARRES2 regulates lipid metabolic reprogramming to mediate the development of brain metastasis in triple negative breast cancer

Background Triple negative breast cancer(TNBC),the most aggressive subtype of breast cancer,is characterized by a high incidence of brain metastasis(BrM)and a poor prognosis.As the most lethal form of breast cancer,BrM remains a major clinical challenge due to its rising incidence and lack of effective treatment strategies.Recent evidence suggested a potential role of lipid metabolic reprogramming in breast cancer brain metastasis(BCBrM),but the underlying mechanisms are far from being fully elucidated.Methods Through analysis of BCBrM transcriptome data from mice and patients,and immunohistochemical validation on patient tissues,we identified and verified the specific down-regulation of retinoic acid receptor responder 2(RARRES2),a multifunctional adipokine and chemokine,in BrM of TNBC.We investigated the effect of aberrant RARRES2 expression of BrM in both in vitro and in vivo studies.Key signaling pathway components were evaluated using multi-omics approaches.Lipidomics were performed to elucidate the regulation of lipid metabolic reprogramming of RARRES2.Results We found that downregulation of RARRES2 is specifically associated with BCBrM,and that RARRES2 deficiency promoted BCBrM through lipid metabolic reprogramming.Mechanistically,reduced expression of RARRES2 in brain metastatic potential TNBC cells resulted in increased levels of glycerophospholipid and decreased levels of triacylglycerols by regulating phosphatase and tensin homologue(PTEN)-mammalian target of rapamycin(mTOR)-sterol regulatory element-binding protein 1(SREBP1)signaling pathway to facilitate the survival of breast cancer cells in the unique brain microenvironment.Conclusions Our work uncovers an essential role of RARRES2 in linking lipid metabolic reprogramming and the development of BrM.RARRES2-dependent metabolic functions may serve as potential biomarkers or therapeutic targets for BCBrM.

Synchronous multiple primary malignant neoplasms in breast,kidney,and bilateral thyroid:A case report

BACKGROUND Multiple primary malignant neoplasms(MPMNs)are rare,while synchronous MPMNs(SMPMNs)are even less common.Owing to the progression of medical technology and the extension of life expectancy,its incidence is gradually increasing.CASE SUMMARY Although reports of breast and thyroid dual cancers are common,cases of an additional diagnosis of kidney primary cancer within the same individual are rare.CONCLUSION We present a case of simultaneous MPMN of three endocrine organs,reviewing the relevant literature to enhance our understanding of SMPMNs while emphasizing the increasingly important need for accurate diagnosis and multidisciplinary management whenever this challenging situation arises.

Targeting metabolism in breast cancer: How far we can go?

Adjuvant therapies for breast cancer have achieved great success in recent years and early breast cancer is now a curable or chronic disease. Targeted therapies, including endocrine therapy and human epidermal growth factor receptor-2 targeted therapy, marked a new era of breast cancer treatment. However, except for chemotherapy, an efficient drug treatment to improve the overall survival of breast cancer patients is still lacking for triple negative breast cancer. Furthermore, a certain proportion of breast cancer patients present with resistance to drug therapy, making it much more difficult to control the deterioration of the disease. Recently, altered energy metabolism has become one of the hallmarks of cancer, including breast cancer, and it may be linked to drug resistance. Targeting cellular metabolism is becoming a promising strategy to overcome drug resistance in cancer therapy. This review discusses metabolic reprogramming in breast cancer and the possible complex mechanism of modulation. We also summarize the recent advances in metabolic therapy targeted glycolysis, glutaminolysis and fatty acids synthesis in breast cancer.

Advance in metabolism and target therapy in breast cancer stem cells

Breast cancer,like many other cancers,is believed to be driven by a population of cells that display stem cell properties.Recent studies suggest that cancer stem cells(CSCs)are essential for tumor progression,and tumor relapse is thought to be caused by the presence of these cells.CSC-targeted therapies have also been proposed to overcome therapeutic resistance in breast cancer after the traditional therapies.Additionally,the metabolic properties of cancer cells differ markedly from those of normal cells.The efficacy of metabolic targeted therapy has been shown to enhance anti-cancer treatment or overcome therapeutic resistance of breast cancer cells.Metabolic targeting of breast CSCs(BCSCs)may be a very effective strategy for anti-cancer treatment of breast cancer cells.Thus,in this review,we focus on discussing the studies involving metabolism and targeted therapy in BCSCs.

Delineation of fatty acid metabolism in gastric cancer:Therapeutic implications

BACKGROUND The prognosis of gastric cancer is extremely poor.Metabolic reprogramming involving lipids has been associated with cancer occurrence and progression.AIM To illustrate fatty acid metabolic mechanisms in gastric cancer,detect core genes,develop a prognostic model,and provide treatment options.METHODS Raw data from The Cancer Genome Atlas and Gene Expression Omnibus databases were collected and analyzed.Differentially expressed fatty acid metabolism genes were identified and incorporated into a risk model based on least absolute shrinkage and selection operator regression analysis.Then,patients from The Cancer Genome Atlas were assigned to high-and low-risk cohorts according to the mean value of the risk score as the threshold,which was verified in the Gene Expression Omnibus database.Relationships between chemotherapeutic sensitivity and tumor microenvironment features were assessed.RESULTS An integrated evaluation was performed in this study.Fatty acid metabolismrelated genes were used to construct the risk model.Patients classified into the high-risk cohort were considered to be resistant to chemotherapy based on results of the“pRRophetic”R package.Patients in the high-risk cohort were associated with type Ⅰ/Ⅱ interferon activation,increased inflammation level,immune cell infiltration,and tumor immune dysfunction based on the exclusion algorithm,indicating the potential benefit of immunotherapy in these patients.CONCLUSION We constructed a fatty acid-related risk score model to assess the comprehensive fatty acid features in gastric cancer and validated its vital role in prognosis,chemotherapy sensitivity,and immunotherapy.

Leptin influences estrogen metabolism and increases DNA adduct formation in breast cancer cells

Objective: The elevated incidence of obesity has been paralleled with higher risks of breast cancer. High adiposity increases leptin secretion from adipose tissue, which in turn increases cancer cell proliferation. The interplay between leptin and estrogen is one of the mechanisms through which leptin influences breast carcinogenesis. An unbalanced estrogen metabolism increases the formations of catechol estrogen quinones, DNA adducts, and cancer mutations. This study aims to investigate the effect of leptin on some estrogen metabolic enzymes and DNA adduction in breast cancer cells.Methods: High performance liquid chromatography(HPLC) was performed to analyze the DNA adducts 4-OHE1[E2]-1-N3 adenine and 4-OHE1[E2]-1-N7 guanine. Reporter gene assay, real time reverse transcription polymerase chain reaction(real time RT-PCR), and Western blot were used to assess the expression of estrogen metabolizing genes and enzymes: Cytochrome P-4501B1(CYP1B1), Nicotinamide adenine dinucleotide phosphate-quinone oxidoreductase1(NQO1), and Catechol-O-methyl transferase(COMT).Results: Leptin significantly increased the DNA adducts 4-OHE1[E2]-1-N3 adenine and 4-OHE1[E2]-1-N7 guanine.Furthermore, leptin significantly upregulated CYP1B1 promoter activity and protein expression. The luciferase promoter activities of NQO1 and m RNA levels were significantly reduced. Moreover, leptin greatly reduced the reporter activities of the COMT-P1 and COMT-P2 promoters and diminished the protein expression of COMT.Conclusions: Leptin increases DNA adduct levels in breast cancer cells partly by affecting key genes and enzymes involved in estrogen metabolism. Thus, increased focus should be directed toward leptin and its effects on the estrogen metabolic pathway as an effective approach against breast cancer.

Manifestation of Key Molecular Genetic Markers in Pharmacocorrection of Endogenous Iron Metabolism in MCF-7 and MCF-7/DDP Human Breast Cancer Cells

Effects of the nanocomposite and its components (magnetic fluid, cisplatin) on the level of endogenous iron exchange and the key links of genetic and epigenetic regulation of apoptotic program of sensitive and resistant MCF-7 cells were examined. We showed genetic and epigenetic mechanisms of action of nanocomposite of magnetic fluid and cisplatin. Nanocomposite caused elevation of number of cells in apoptosis in sensitive and especially resistant MCF-7 cells compared to cisplatin alone. It was proved that impact of nanocomposite on MCF-7/S and MCF-7/DDP cells caused more significant changes in expression of apoptosis regulators p53, Bcl-2 and Bax. We also suggested that changes in endogenous iron homeostasis and activation of free radical processes caused significant impact on apoptosis. Those changes included changes in methylation and expression of transferrin, its receptors, ferritin heavy and light chains (predominantly in resistant cell line), which caused activation of free radical synthesis and development of oxidative stress. We also showed that nanocomposite impact resulted into significant changes in expression of miRNA-34a and miRNA-200b, which regulated apoptosis, cell adhesion, invasion and activity of ferritin heavy chains gene. Thus, use of nanocomposite containing cisplatin and ferromagnetic as exogenous source of Fe ions caused changes of endogenous iron levels in sensitive and resistant cells allowing to increase specific activity of cytostatics and overcome factors, which promoted MDR development. Pharmacocorrection of endogenous iron metabolism allowed increasing antitumor activity of cisplatin and overcoming drug resistance.

Glucose Metabolism in Breast Cancer and its Implication in Cancer Therapy

It is well known that malignant cells have accelerated glucose uptake and metabolism in order to maintain their fast proliferation rates. With the increased influx of glucose into cancer cells, glycolysis is facilitated through a coordinated regulation of metabolic enzymes and pyruvate consumption. Shiftting from mitochondrial oxidative phosphorylation to glycolysis and other pathways such as pentose phosphate pathway (PPP) and de novo fatty acid synthesis in the breast tumor provides not only energy but also the materials needed for cell proliferation. Glucose augmentation in tumor cells can be due to the elevated level of glucose transporter (GLUT) proteins, such as the over-expression of GLUT1 and expression of GLUT5 in breast cancers. Moreover, other factors such as hypoxia-inducible factor-1 (HIF-1), estrogen and growth factors are important modulators of glucose metabolism in the progression of breast carcinomas. Therapies targeting at the glycolytic pathway, fatty acid synthesis and GLUTs expression are currently being investigated. Restoring tumor cells to its normal glucose metabolic state would endow tumor specific and accessible treatment that targets glucose metabolism.

Violence against Women with Breast Neoplasms

The aim of this study is to assess the occurrence and type of violence suffered by women with breast cancer in the High Complexity Care Unit of a municipality in the South of Minas and patients in a support group of the University of the South of Minas Gerais. For that aim, a descriptive-exploratory methodology was applied through the quantitative method. Data were collected through a semi-structured form applied in individual interviews over a period of three months. We interviewed 57 patients and among those, 20 women （35.08%） reported having experienced some form of violence at some stage of their life, and the most frequently mentioned was the psychological violence followed by physical aggression. Although it was possible to identify that violence against affected these women, complaints against the aggressor were not affected.

The accuracy of magnetic resonance imaging and ultrasound in evaluating the size of early-stage breast neoplasms

Objective Breast cancer is the most frequently diagnosed cancer in women. Accurate evaluation of the size and extent of the tumor is crucial in selecting a suitable surgical method for patients with breast cancer. Both overestimation and underestimation have important adverse effects on patient care. This study aimed to evaluate the accuracy of breast magnetic resonance imaging(MRI) and ultrasound(US) examination for measuring the size and extent of early-stage breast neoplasms.Methods The longest diameter of breast tumors in patients with T_(1–2)N_(0–1)M_0 invasive breast cancer preparing for breast-conserving surgery(BCS) was measured preoperatively by using both MRI and US and their accuracy was compared with that of postoperative pathologic examination. If the diameter difference was within 2 mm, it was considered to be consistent with pathologic examination.Results A total of 36 patients were imaged using both MRI and US. The mean longest diameter of the tumors on MRI, US, and postoperative pathologic examination was 20.86 mm ± 4.09 mm(range: 11–27 mm), 16.14 mm ± 4.91 mm(range: 6–26 mm), and 18.36 mm ± 3.88 mm(range: 9–24 mm). US examination underestimated the size of the tumor compared to that determined using pathologic examination(t = 3.49, P < 0.01), while MRI overestimated it(t =-6.35, P < 0.01). The linear correlation coefficients between the image measurements and pathologic tumor size were r = 0.826(P < 0.01) for MRI and r = 0.645(P < 0.01) for US. The rate of consistency of MRI and US compared to that with pathologic examination was 88.89% and 80.65%, respectively, and there was no statistically significant difference between them(χ~2 = 0.80, P > 0.05).Conclusion MRI and US are both effective methods to assess the size of breast tumors, and they maintain good consistency with pathologic examination. MRI has a better correlation with pathology. However, we should be careful about the risk of inaccurate size estimation.

Single-cell transcriptomic atlas reveals immune and metabolism perturbation of depression in the pathogenesis of breast cancer

Epidemiological evidence indicates that major depressive disorder(MDD)may predispose the development and prognosis of breast cancer(BC)in females[1].However,the mechanisms linking these phenotypes are not fully understood.Chronic stress,a hallmark of depression,has been underscored to affect anti-tumor immunity,tumor metabolic reprogramming,hormone synthesis in BC[2,3],and increase tumor metastasis[4],but there is a lack of detailed cellular-level characterization of how MDD history affects the tumorigenesis of BC.This study explored the single-cell atlas of multiple tissues from BC patients with and without a history of MDD for characterizing the potential molecular alternations in their tumorigenesis(Figure 1A).

Metabolic reprogramming in triple-negative breast cancer

Since triple-negative breast cancer(TNBC)was first defined over a decade ago,increasing studies have focused on its genetic and molecular characteristics.Patients diagnosed with TNBC,compared to those diagnosed with other breast cancer subtypes,have relatively poor outcomes due to high tumor aggressiveness and lack of targeted treatment.Metabolic reprogramming,an emerging hallmark of cancer,is hijacked by TNBC to fulfill bioenergetic and biosynthetic demands;maintain the redox balance;and further promote oncogenic signaling,cell proliferation,and metastasis.Understanding the mechanisms of metabolic remodeling may guide the design of metabolic strategies for the effective intervention of TNBC.Here,we review the metabolic reprogramming of glycolysis,oxidative phosphorylation,amino acid metabolism,lipid metabolism,and other branched pathways in TNBC and explore opportunities for new biomarkers,imaging modalities,and metabolically targeted therapies.

Understanding the mechanisms underlying obesity in remodeling the breast tumor immune microenvironment:from the perspective of inflammation

Obesity is a well-known modifiable risk factor for breast cancer and is considered a poor prognostic factor in pre-and post-menopausal women.While the systemic effects of obesity have been extensively studied,less is known about the mechanisms underlying obesityassociated cancer risk and the local consequences of obesity.Thus,obesity-induced inflammation has become the focus of research interest.Biologically,the development of cancer involves a complex interaction with numerous components.As the tumor immune microenvironment changes due to obesity-triggered inflammation,an increase in infiltration occurs for proinflammatory cytokines and adipokines,as well as adipocytes,immune cells,and tumor cells in the expanded adipose tissue.Complicated cellular-molecular crosstalk networks change critical pathways,mediate metabolic and immune function reprogramming,and have a significant role in tumor metastasis,proliferation,resistance,angiogenesis,and tumorigenesis.This review summarizes recent research findings on how inflammatory mediators in the in situ tumor microenvironment regulate the occurrence and development of breast cancer in the context of obesity.We analyzed the heterogeneity and potential mechanisms of the breast cancer immune microenvironment from the perspective of inflammation to provide a reference for the clinical transformation of precision targeted cancer therapy.

Breast cancer: Epidemiology, risk factors and screening

Breast cancer is a global health concern with a significant impact on the well-being of women. Worldwide, the past several decades have witnessed changes in the incidence and mortality of breast cancer. Additionally,epidemiological data reveal distinct geographic and demographic disparities globally. A range of modifiable and non-modifiable risk factors are established as being associated with an increased risk of developing breast cancer.This review discusses genetic, hormonal, behavioral, environmental, and breast-related risk factors. Screening plays a critical role in the effective management of breast cancer. Various screening modalities, including mammography,ultrasound, magnetic resonance imaging(MRI), and physical examination, have different applications, and a combination of these modalities is applied in practice. Current screening recommendations are based on factors including age and risk, with a significant emphasis on minimizing potential harms to achieve an optimal benefits-to-harms ratio. This review provides a comprehensive insight into the epidemiology, risk factors, and screening of breast cancer. Understanding these elements is crucial for improving breast cancer management and reducing its burden on affected individuals and healthcare systems.

Presence of circulating tumor cells is associated with metabolic-related variables in postoperative patients with early-stage breast cancer

Objective：Although circulating tumor cells（CTCs）have been well-established as promising prognostic biomarkers in both early breast cancer and metastatic settings,little is known regarding the prognostic relevance of CTCs in the long-term postoperative monitoring of patients with non-metastatic breast cancer（non-MBC）.In this study,we investigated the associations of CTCs with clinicopathological features and metabolic-related variables,such as obesity and hyperglycemia.Methods：In this retrospective study,we recruited 264 patients with postoperative stage Ⅰ–Ⅲ breast cancer at Guangdong General Hospital from January 2009 to December 2015.The prevalence and number of CTCs were assessed using the Cell Search System at a median time of 19.0 months[interquartile range（IQR）,7.8–33.0]after surgery.The CTC assay results were correlated with the clinicopathological features and metabolic-related variables.A multivariate logistic regression analysis was performed to further determine the independent predictors of CTCs.Results：CTCs were detected in 10.6%of all patients.The positive rate of CTCs in patients with infiltrating ductal carcinoma was lower than that in patients with other pathological types（9.0%vs.28.6%,P=0.020）.More importantly,the presence of CTCs was correlated with blood glucose level（P=0.015）and high-density lipoprotein level（P=0.030）.The multivariate logistic regression analysis showed that the pathological type[odds ratio（OR）：1.757,95%CI：1.021–3.023;P=0.042]and blood glucose level（OR：1.218,95%CI：1.014–1.465;P=0.035）were independent predictors of the presence of CTCs.Conclusions：This study revealed potential associations between CTCs and metabolic-related factors in Chinese patients with non-MBC and supports the hypothesis that metabolic dysfunction in breast cancer patients might influence the biological activity of metastatic breast cancer,leading to a higher prevalence of CTCs.

Breast reconstruction:Review of current autologous and implantbased techniques and long-term oncologic outcome

Implant-based reconstruction is the most common method of breast reconstruction.Autologous breast reconstruction is an indispensable option for breast reconstruction demanding keen microsurgical skills and robust anatomical understanding.The reconstructive choice is made by the patient after a discussion with the plastic surgeon covering all the available options.Advantages and disadvantages of each technique along with long-term oncologic outcome are reviewed.

Diffusion tensor imaging and proton magnetic resonance spectroscopy in brain tumor Correlation between structure and metabolism

Proton magnetic resonance spectroscopy and diffusion tensor imaging are non-invasive techniques used to detect metabolites and water diffusion in vivo. Previous studies have confirmed a positive correlation of individual fractional anisotropy values with N-acetylaspartate/creatine and N-acetylaspartate/choline ratios in tumors, edema, and normal white matter. This study divided the brain parenchyma into tumor, pedtumoral edema, and normal-appearing white matter according to MRI data, and analyzed the correlation of metabolites with water molecular diffusion. Results demonstrated that in normal-appearing white matter, N-acetylaspartate/creatine ratios were positively correlated with fractional anisotropy values, negatively correlated with radial diffusivities, and positively correlated with maximum eigenvalues. Maximum eigenvalues and radial diffusivities in peritumoral edema showed a negative correlation with choline, N-acetylaspartate, and creatine. Radial diffusivities in tumor demonstrated a negative correlation with choline. These data suggest that the relationship between metabolism and structure is markedly changed from normal white matter to peritumoral edema and tumor. Neural metabolism in the peritumoral edema area decreased with expanding extracellular space. The normal relationship of neural function and microstructure disappeared in the tumor region.

The Anti-Tumor Effect of a High Caloric Diet in the PyMT Mouse Breast Cancer Model Is Initiated by an Increase in Metabolic Rate

Obesity is associated with an increased risk of mortality from certain types of cancer, including cancer of the breast. Because obesity is associated with multiple risk factors, however, the exact reasons remain unclear. The objective of this study was to determine which of the risk factors associated with obesity are related to enhanced tumor development. The MMTV-PyMT mouse model develops mammary tumors which share numerous characteristics with those of humans. We challenged these mice with a high fat/high carbohydrate, high caloric (HC) diet, and looked for relationships between enhanced primary tumor development and adiposity, various aspects of glucose homeostasis, and metabolic factors. The HC diet enhanced tumor progression in PyMT mice. While mice on the HC diet also developed increased adiposity, hyperglycemia and hyperinsulinemia, none of these risk factors was found to be associated with the observed increases in tumor growth. Rather, we found that while overall, tumor growth was enhanced in HC diet-fed mice compared to those maintained on a regular diet, it was attenuated in individuals by an HC diet-induced increase in metabolic rate and decrease in respiratory exchange ratio. Tumor size in HC diet-fed mice was directly related to p38 phosphorylation and Bcl-2 inhibition, and the degree of vascularization of these tumors was closely and indirectly related to the rate of mouse oxygen consumption. The data suggest that an increase in metabolic rate and oxygen consumption, induced by the introduction of a high caloric diet, has a protective effect against tumor growth by increasing the activity levels of the tumor suppressor p38 and decreasing the activity of the antiapoptoic protein Bcl-2, as well as by reducing hypoxia-induced tumor vascularization.

Granular cell tumor of the breast:A case report and review of literature

BACKGROUND Granular cell tumor(GCT)of the breast(GCTB)is a rare neoplasm that can exhibit malignant characteristics both clinically and radiologically.This tumor can also coexist and colocalize with breast carcinoma.CASE SUMMARY We present a patient with this uncommon tumor and discuss the diagnostic and therapeutic approaches in order to further the knowledge of GCTB and prevent misdiagnosis and overtreatment.The characteristics of the tumor,methods of diagnosis,therapy and postoperative pathological outcomes were analyzed,and relevant literatures of GCTs were reviewed.The patient underwent surgery after core needle biopsy,and the excised neoplasm was sent for pathological examination.Histological analysis revealed nests of cells with abundant pink granular cytoplasm,confirming the diagnosis of GCTB.CONCLUSION As manifestations of GCT and malignancy can mimic each other,a careful histological examination is essential before major surgery.Treatment consisting of complete excision with close clinical follow-up is recommended.