Nonlinear dynamics of estrogen receptor-positive breast cancer integrating experimental data: A novel spatial modeling approach.

Oncology research has focused extensively on estrogen hormones and their function in breast cancer proliferation. Mathematical modeling is essential for the analysis and simulation of breast cancers. This research presents a novel approach to examine the therapeutic and inhibitory effects of hormone and estrogen therapies on the onset of breast cancer. Our proposed mathematical model comprises a nonlinear coupled system of partial differential equations, capturing intricate interactions among estrogen, cytotoxic T lymphocytes, dormant cancer cells, and active cancer cells. The model's parameters are meticulously estimated through experimental studies, and we conduct a comprehensive global sensitivity analysis to assess the uncertainty of these parameter values. Remarkably, our findings underscore the pivotal role of hormone therapy in curtailing breast tumor growth by blocking estrogen's influence on cancer cells. Beyond this crucial insight, our proposed model offers an integrated framework to delve into the complexity of tumor progression and immune response under hormone therapy. We employ diverse experimental datasets encompassing gene expression profiles, spatial tumor morphology, and cellular interactions. Integrating multidimensional experimental data with mathematical models enhances our understanding of breast cancer dynamics and paves the way for personalized treatment strategies. Our study advances our comprehension of estrogen receptor-positive breast cancer and exemplifies a transformative approach that merges experimental data with cutting-edge mathematical modeling. This framework promises to illuminate the complexities of cancer progression and therapy, with broad implications for oncology.

Clinician perspectives on patient-centered conversations about weight management with patients with early breast cancer.

BACKGROUND: The aim of this study is to gather detailed insights from breast cancer (BC) clinicians on how to have patient-centered conversations about weight and weight management with women diagnosed with early BC. A high body mass index (BMI) is a risk factor for female BC, and many women diagnosed with BC experience unhealthy weight gain after their primary treatment. The oncology team has the opportunity to discuss the importance of healthy weight for BC prognosis and survival. METHODS: The sample of community-based BC clinicians included the following: three Black clinicians, three White clinicians, and two clinicians who were neither Black nor White; six females and two males; and six MDs and two physician assistants or nurse practitioners. Semistructured telephone interviews were conducted with these clinicians regarding their experience with and insights into having healthy weight conversations during routine clinic visits. RESULTS: Clinicians noted that weight-related conversations should focus less on BMI and weight loss and more on "healthy behavior." Clinicians looked for cues from their patients as to when they were ready for "healthy weight" counseling, receptive to diet/nutrition counseling and referrals, and ready to attempt behavioral change. Clinicians noted that encouraging physical activity could be especially challenging with patients accustomed to a sedentary lifestyle. CONCLUSIONS: Clinic-based conversations about healthy weight are likely to be most productive for both patients and their treating oncologists during the post-primary treatment phase when patients are most receptive to behavioral change that enhances their prognosis and survival.

Home-based exercise improves quality of life in breast and prostate cancer survivors: A meta-analysis.

BACKGROUND: Breast (BCa) and prostate (PCa) cancer are two of the most common but survivable cancers. One important component of survivorship that is impacted by treatment long term is diminished quality of life (QoL). Supervised exercise improves QoL and subsequent outcomes but is not accessible for all survivors. Additionally, many factors influence QoL including physical activity (PA), cardiorespiratory fitness (CRF), physical function, and fatigue. However, the COVID-19 pandemic has highlighted the need to increase access to exercise beyond supervised exercise facilities. Home-based exercise may provide a feasible alternative for cancer survivors especially for those living in rural communities. OBJECTIVES: The primary aim is to investigate the effects of home-based exercise training (Pre-training vs. Post-training) on QoL in BCa/PCa. A secondary aim is to investigate PA, CRF, physical function, and fatigue and potential moderators (age, cancer-type, intervention duration and type). Home-based exercise trials (randomized crossover or quasi-experimental design) with adults (aged 18 years and over) breast or prostate cancer survivors (not currently undergoing chemotherapy or radiation treatment) were eligible for inclusion. DATA SOURCES: Electronic databases were searched (inception-December 2022) for studies which included adult BCa or PCa survivors (not currently on chemotherapy/radiation), at least measured QoL, and undergoing unsupervised, home-based exercise training. APPRAISAL AND SYNTHESIS METHODS: Initially, 819 studies were identified, from which 17 studies (20 effects) involving 692 participants were extracted. Effect sizes were calculated as standardized mean differences (SMD). Data were pooled using a 3-level model with restricted maximum likelihood estimation. Pooled SMD was used to assess the magnitude of effect, where <0.2, 0.2, 0.5, and 0.8 was defined as trivial, small, moderate, and large respectively. RESULTS: Home-based exercise resulted in small improvements in QoL (SMD = 0.30, 95% CI 0.01, 0.60, p = 0.042), PA (SMD = 0.49, 95% CI 0.26, 0.75, p<0.001) and CRF (SMD = 0.45, 95% CI -0.01, 0.91, p = 0.056). Physical function (SMD = 0.00, 95% CI -0.21, 0.21, p = 1.000) and fatigue (SMD = -0.61, 95%CI -1.53, 0.32, p = 0.198) did not change. CONCLUSIONS: Home-based exercise results in small improves QoL in BCa/PCa survivors, independent of cancer type, intervention duration and type, or age. Home-based exercise also improves PA and CRF enhancing survivorship. Therefore, home-based exercise is an efficacious alternative option to improve QoL for BCa and PCa survivors especially for those who live in rural communities or lack access to exercise facilities.

Association between major discrimination and deficit accumulation in African American cancer survivors: The Detroit Research on Cancer Survivors Study.

BACKGROUND: Discrimination can adversely affect health and accelerate aging, but little is known about these relationships in cancer survivors. This study examines associations of discrimination and aging among self-identified African American survivors. METHODS: A population-based sample of 2232 survivors 20-79 years old at diagnosis were enrolled within 5 years of breast (n = 787), colorectal (n = 227), lung (n = 223), or prostate (n = 995) cancer between 2017 and 2022. Surveys were completed post-active therapy. A deficit accumulation index measured aging-related disease and function (score range, 0-1, where <0.20 is robust, 0.20 to <0.35 is pre-frail, and 0.35+ is frail; 0.06 is a large clinically meaningful difference). The discrimination scale assessed ever experiencing major discrimination and seven types of events (score, 0-7). Linear regression tested the association of discrimination and deficit accumulation, controlling for age, time from diagnosis, cancer type, stage and therapy, and sociodemographic variables. RESULTS: Survivors were an average of 62 years old (SD, 9.6), 63.2% reported ever experiencing major discrimination, with an average of 2.4 (SD, 1.7) types of discrimination events. Only 24.4% had deficit accumulation scores considered robust (mean score, 0.30 [SD, 0.13]). Among those who reported ever experiencing major discrimination, survivors with four to seven types of discrimination events (vs. 0-1) had a large, clinically meaningful increase in adjusted deficits (0.062, p < .001) and this pattern was consistent across cancer types. CONCLUSION: African American cancer survivors have high deficit accumulated index scores, and experiences of major discrimination were positively associated with these deficits. Future studies are needed to understand the intersectionality between aging, discrimination, and cancer survivorship among diverse populations.

Exposición a material particulado y su relación con el cáncer de mama. Mecanismos fisiopatológicos / Exposure to particulate matter and its association to breast cancer. Pathophysiological mechanisms

Introducción. El cáncer de mama es el tipo de cáncer que genera más muertes en mujeres en el mundo. Aunque se reconoce el aporte de factores genéticos, hormonales y de estilos de vida como sus principales causas, las hipótesis que señalan que la contaminación del ambiente juega un papel importante en su desarrollo, han tomado mucha fuerza en los últimos años. Estas hipótesis surgen debido a que el aumento en la incidencia del cáncer de mama coincide con procesos de industrialización, además de mayor presencia en regiones urbanas y con altos niveles de contaminación. El objetivo de este artículo fue consolidar información sobre los mecanismos fisiopatológicos que puedan explicar la relación entre cáncer de mama y la contaminación por material particulado. Metodología. Se realizó una búsqueda de literatura en PubMed, Google Académico y Epistemonikos para documentos publicados sobre el tema desde enero de 2016 hasta el 3 de agosto de 2022. Resultados. Se encontró que algunos de los mecanismos que podrían explicar dicha relación incluyen: alteraciones endocrinas que favorecen cambios hormonales, induciendo el crecimiento mamario; cambios en las características histológicas del tejido normal, como involución reducida de unidades lobulares ductales terminales; formación de aductos de hidrocarburos aromáticos policíclicos-ácido desoxirribonucleico (HAP-ADN), con mutación específica del gen TP53; activación de la proliferación en la línea celular MCF-7; y, alteraciones en la metilación del ADN. Conclusión. Si bien órganos distales como la mama no son la primera entrada de los contaminantes ambientales al cuerpo, estos sí pueden verse afectados tras la exposición a largo plazo, a través de diferentes mecanismos de disrupción endocrina y daño al ADN principalmente

Breast cancer is the type of cancer that causes the most deaths in women worldwide. Although the contribution of genetic, hormonal and lifestyle factors are recognized as its main causes, the hypotheses that indicate that environmental pollution has an important role in its development have taken on great strength during the last years. These hypotheses are based on the increase in the incidence of breast cancer that coincides with industrialization processes, in addition to its greater presence in urban regions with high levels of pollution. The aim of this study was to consolidate information on the pathophysiological mechanisms that can explain the relationship between breast cancer and air pollution by particulate matter. Methodology. A literature search was carried out in PubMed, Google Scholar and Epistemonikos for documents published on this topic from January 2016 until August 3rd 2022. Results. Some of the mechanisms that could explain this association include endocrine alterations that favor hormonal changes, inducing breast growth; changes in the histological characteristics of normal tissue such as reduced involution of terminal duct lobular units; formation of polycyclic aromatic hydrocarbons-deoxyribonucleic acid (PAH-DNA) adducts, with specific mutation of the TP53 gene; an increase in cell proliferation in the MCF-7 cell line; and alterations in DNA methylation. Conclusion. Although distal organs such as the breast are not the entry site of environmental pollutants into the body, they can be affected after prolonged exposure, mainly through different mechanisms of endocrine disruption and DNA damage

Systemic Immune Dysregulation in Early Breast Cancer Is Associated With Decreased Plasma Levels of Both Soluble Co-Inhibitory and Co-Stimulatory Immune Checkpoint Molecules.

Breast cancer cells exploit the up-regulation or down-regulation of immune checkpoint proteins to evade anti-tumor immune responses. To explore the possible involvement of this mechanism in promoting systemic immunosuppression, the pre-treatment levels of soluble co-inhibitory and co-stimulatory immune checkpoint molecules, as well as those of cytokines, chemokines, and growth factors were measured in 98 newly diagnosed breast cancer patients and compared with those of 45 healthy controls using multiplex bead array and ELISA technologies. Plasma concentrations of the co-stimulatory immune checkpoints, GITR, GITRL, CD27, CD28, CD40, CD80, CD86 and ICOS, as well as the co-inhibitory molecules, PD-L1, CTLA-4 and TIM-3, were all significantly lower in early breast cancer patients compared to healthy controls, as were those of HVEM and sTLR-2, whereas the plasma concentrations of CX3CL1 (fractalkine), CCL5 (RANTES) and those of the growth factors, M-CSF, FGF-21 and GDF-15 were significantly increased. However, when analyzed according to the patients' breast cancer characteristics, these being triple negative breast cancer (TNBC) vs. non-TNBC, tumor size, stage, nodal status and age, no significant differences were detected between the plasma levels of the various immune checkpoint molecules, cytokines, chemokines and growth factors. Additionally, none of these biomarkers correlated with pathological complete response. This study has identified low plasma levels of soluble co-stimulatory and co-inhibitory immune checkpoint molecules in newly diagnosed, non-metastatic breast cancer patients compared to healthy controls, which is a novel finding seemingly consistent with a state of systemic immune dysregulation. Plausible mechanisms include an association with elevated levels of M-CSF and CCL5, implicating the involvement of immune suppressor cells of the M2-macrophage/monocyte phenotype as possible drivers of this state of systemic immune quiescence/dysregulation.

Resveratrol drives cancer cell senescence via enhancing p38MAPK and DLC1 expressions.

Pro-senescence therapy is a recently proposed anti-cancer strategy and has been shown to effectively inhibit cancer. Resveratrol is gaining attention for its cancer preventive and suppressive properties. The mechanisms of resveratrol in cancer suppression by inducing cancer cell senescence are unclear. Our results showed that resveratrol induced cell senescence along with an increase of SA-ß-Gal activity and inhibition of colony formation in breast and lung cancer cells. The underlying mechanisms were that resveratrol induced ER-stress by increasing SIRT1 to promote p38MAPK expression and by reducing NO level to up-regulate DLC1 expression, and ER-stress further resulted in DNA damage and mitochondrial dysfunction, eventually leading to cancer cell senescence. Our findings on resveratrol's induction of cancer cell senescence via activating ER-stress through the SIRT1/p38MAPK and NO/DLC1 pathways provide a solid base for its clinical application and its preventive application as a food additive.

Prognostic significance of the skeletal muscle index and systemic inflammatory index in patients with lymph node-positive breast cancer after radical mastectomy.

BACKGROUND: The role of skeletal muscle index (SMI) and systemic inflammation index (SII) for patients with lymph node-positive breast cancer remain controversial. This retrospective study aims to evaluate the individual and synergistic value of SMI and SII in outcomes prediction in this population. METHODS: Lymph node-positive breast cancer patients who received mastectomy between January 2011 and February 2013 were included in this retrospective study. We used abdominal computed tomography (CT) to measure skeletal muscle mass at the third lumbar (L3) level. The optimal cut-off values of SMI and SII were determined through maximizing the Youden index on the receiver operating characteristic (ROC) curves. Kaplan-Meier method was used to assess the correlation between SMI, SII, and overall survival (OS). The prognostic value of SMI and SII were analyzed with the multivariable Cox proportional hazards model. RESULTS: Of 97 patients included in our study (mean age: 46 [range: 27-73] years; median follow-up: 62.5 months), 71 had low SMI (sarcopenia), 59 had low SII, and 56 had low SMI + SII. Kaplan-Meier survival curves showed that both high SMI (P = 0.021, 5-year OS: 84.0% vs. 94.1%) and high SII (P = 0.043, 5-year OS: 81.0% vs. 97.3%) were associated with worse OS. Additionally, patients with either low SMI or low SII had significantly better OS (P = 0.0059, 5-year OS: 100.0% vs. 84.6%) than those with high SMI + SII. Multivariable analysis confirmed the predictive values of high SMI (P = 0.024, hazard ratio [HR]: 9.87) and high SII (P = 0.048, HR: 6.87) for poor OS. Moreover, high SMI + SII was significantly associated with poor survival (P = 0.016, HR: 16.36). CONCLUSIONS: In this retrospective analysis, both SMI and SII independently predicted the prognosis of patients with lymph node-positive breast cancer. SMI + SII might be a stronger prognostic factor than either alone based on our findings, but should be further verified in a larger study.

Aberrant epigenetic and transcriptional events associated with breast cancer risk.

BACKGROUND: Genome-wide association studies have identified several breast cancer susceptibility loci. However, biomarkers for risk assessment are still missing. Here, we investigated cancer-related molecular changes detected in tissues from women at high risk for breast cancer prior to disease manifestation. Disease-free breast tissue cores donated by healthy women (N = 146, median age = 39 years) were processed for both methylome (MethylCap) and transcriptome (Illumina's HiSeq4000) sequencing. Analysis of tissue microarray and primary breast epithelial cells was used to confirm gene expression dysregulation. RESULTS: Transcriptomic analysis identified 69 differentially expressed genes between women at high and those at average risk of breast cancer (Tyrer-Cuzick model) at FDR < 0.05 and fold change ≥ 2. Majority of the identified genes were involved in DNA damage checkpoint, cell cycle, and cell adhesion. Two genes, FAM83A and NEK2, were overexpressed in tissue sections (FDR < 0.01) and primary epithelial cells (p < 0.05) from high-risk breasts. Moreover, 1698 DNA methylation changes were identified in high-risk breast tissues (FDR < 0.05), partially overlapped with cancer-related signatures, and correlated with transcriptional changes (p < 0.05, r ≤ 0.5). Finally, among the participants, 35 women donated breast biopsies at two time points, and age-related molecular alterations enhanced in high-risk subjects were identified. CONCLUSIONS: Normal breast tissue from women at high risk of breast cancer bears molecular aberrations that may contribute to breast cancer susceptibility. This study is the first molecular characterization of the true normal breast tissues, and provides an opportunity to investigate molecular markers of breast cancer risk, which may lead to new preventive approaches.

Clinical characteristics, pregnancy outcomes and ovarian function of pregnancy-associated breast cancer patients: a retrospective age-matched study.

BACKGROUND: Pregnancy-associated breast cancer (PABC) is a rare disease with increasing incidence. The prognosis, pregnancy outcomes and subsequent ovarian function of PABC patients are attracting attention. METHODS: Sixty-three PABC patients and 126 age-matched non-PABC patients were obtained in Tongji Hospital from January 2011 to September 2019. The clinical characteristics and ovarian function of PABC patients were compared with those of non-PABC patients. The pregnancy outcomes and neonatal outcomes of patients with breast cancer diagnosed during pregnancy (BCP) were described. Nonparametric tests, the χ2-test Kaplan-Meier, Cox regression and binomial logistic regression were used for analysis. RESULTS: PABC patients were diagnosed with a more advanced tumour stage (II: 47.6% vs. 45.2%, III: 33.3% vs. 19.8%, IV 3.2% vs. 0%, p = 0.003), which caused worse progression-free survival (PFS) (log-rank p = 0.0138) and breast cancer-specific survival (CSS) (log-rank p = 0.0076) than non-PABC patients. Tumour stage (III/IV vs. 0/I/II) (HR 16.017, 95% CI 5.830 ~ 44.006, p < 0.001) and endocrine therapy (HR 0.254, 95% CI 0.099 ~ 0.653, p = 0.004) were predictors of PFS. Tumour stage (III/IV vs. 0/I/II) (HR 30.875, 95% CI 7.232 ~ 131.820, p < 0.001), endocrine therapy (HR 0.200, 95% CI 0.049 ~ 0.818, p = 0.025) and targeted therapy (HR 0.143, 95% CI 0.028 ~ 0.743, p = 0.021) were predictors for breast CSS. Among the 15 BCP patients, 11 patients voluntarily continued their pregnancy, and the newborns had no obvious birth defects, either in 5 patients who received chemotherapy or in 6 patients who did not receive chemotherapy during pregnancy. Among the patients who received chemotherapy and did not receive endocrine therapy, 24 PABC patients and 48 non-PABC patients experienced chemotherapy-induced amenorrhea. There was no significant difference in resumption of menstruation between the two groups at 6 months and 12 months after the end of chemotherapy. No potential factors affecting resumption of menstruation were found. CONCLUSION: Pregnancy at diagnosis or within 1 year after delivery was not a risk factor for a worse prognosis in PABC patients. Compared with non-PABC patients, patients with PABC presented more aggressive tumour characteristics, which could mostly explain the worse prognosis observed in PABC patients. Receiving the appropriate regimen of chemotherapy in the second and third trimesters did not affect the maternal outcomes or neonatal outcomes of BCP patients. The special physiological state during pregnancy and lactation did not interfere with the damage of chemotherapy to ovarian function.

Cold Atmospheric Plasma Apoptotic and Oxidative Effects on MCF7 and HCC1806 Human Breast Cancer Cells.

Breast cancer (BC) is a malignant neoplasia with the highest incidence and mortality rates in women worldwide. Currently, therapies include surgery, radiotherapy, and chemotherapy, including targeted therapies in some cases. However, treatments are often associated with serious adverse effects. Looking for new options in BC treatment, we evaluated the therapeutic potential of cold atmospheric plasma (CAP) in two cell lines (MCF7 and HCC1806) with distinct histological features. Apoptosis seemed to be the most prevalent type of death, as corroborated by several biochemical features, including phosphatidylserine exposure, the disruption of mitochondrial membrane potential, an increase in BAX/BCL2 ratio and procaspase 3 loss. Moreover, the accumulation of cells in the G2/M phase of the cell cycle points to the loss of replication ability and decreased survival. Despite reported toxic concentrations of peroxides in culture media exposed to plasma, intracellular peroxide concentration was overall decreased accompanying a reduction in GSH levels shortly after plasma exposure in both cell lines. In HCC1806, elevated nitric oxide (NO) concentration accompanied by reduced superoxide levels suggests that these cells are capable of converting plasma-derived nitrites into NO that competes with superoxide dismutase (SOD) for superoxide to form peroxinitrite. The concomitant inhibition of the antioxidative activity of cells during CAP treatment, particularly the inhibition of cytochrome c oxidase with sodium azide, synergistically increased plasma toxicity. Thus, this in vitro research enlightens the therapeutic potential of CAP in the treatment of breast cancer, elucidating its possible mechanisms of action.

Function of miRNA-145-5p in the pathogenesis of human disorders.

miR-145-5p is a microRNA whose role in diverse disorders has been verified. This miRNA is encoded by MIR145 gene on chromosome 5. This miRNA is mainly considered as a tumor suppressor miRNA in diverse types of cancers, including bladder cancer, breast cancer, cervical cancer, cholangiocarcinoma, renal cancer, and gastrointestinal cancers. However, few studies have reported up-regulation of this miRNA in some cancers. Moreover, it has been shown to affect pathogenesis of a number of non-malignant conditions such as aplastic anemia, asthma, cerebral ischemia/reperfusion injury, diabetic nephropathy, rheumatoid arthritis and Sjögren syndrome. In the current review, we summarize the available literature about the role of miR-145-5p in these conditions.

Genomic landscape of secretory carcinoma of the breast with axillary lymph node metastasis.

OBJECTIVE: Secretory carcinoma of the breast (SCB) is a rare low-grade often triple-negative breast carcinoma. We aim to analyze the pathological and molecular features of 21 SCBs, especially the SCBs with axillary lymph node metastasis. METHODS: The clinicopathological characteristics of 21 SCBs were reviewed. Breast biomarkers, Pan-TRK and ETV6 break, and ETV6-NTRK3 fusion were performed on all cases. Next-Generation Sequencing (NGS) was performed on two cases with lymph node metastasis. RESULTS: 21 SCBs consisted of 2 men and 19 women aged 5～73 years (median 43 years), with a mean 2.1 cm (range 0.5～3.5 cm) tumor size. 90.1% (19/21) cases had mixed microcystic, solid, tubular, and papillary patterns. Pan-TRK and S100 are positive in 95% (20/21) and 90% (19/21) of cases, respectively. Tumor markers ER, PR, and HER2 expressions were 62% (13/21), 33% (7/21), and 0% (0/21). All cases showed ETV6 (21/21) rearrangement and ETV6-NTRK3 (11/11) fusion. 57% (12/21) of the cases had a balanced translocation and 38% (8/21) with unbalanced signals of ETV6. There was no clinical difference between balanced and unbalanced translocations in histological morphology and other prognosis factors. Furthermore, one case (#4) had a duplication of the ETV6 gene and presented axillary lymph node metastasis. NGS analysis revealed simple genomes, low tumor mutation burden, stable microsatellite sites, and single nucleotide polymorphism (SNP) heterozygous mutation in both SCBs with nodal metastasis. CONCLUSION: SCB is an indolent invasive carcinoma, even the cases with axillary lymph node metastasis, presenting simple genomes. Duplication of ETV6 cases may indicate lymph node metastasis.

Knockdown of nuclear receptor binding SET domain-containing protein 1 (NSD1) inhibits proliferation and facilitates apoptosis in paclitaxel-resistant breast cancer cells via inactivating the Wnt/ß-catenin signaling pathway.

The burden of breast cancer (BC) has exacerbated over decades. Paclitaxel resistance is responsible for increasing BC treatment burden. Nuclear receptor binding SET domain-containing protein 1 (NSD1) is positively correlated with a poor prognosis in patients with BC. This study investigates the function of NSD1 in paclitaxel-resistant (PR) BC cells. The high levels of NSD1 and Wnt10b in PR BC cell lines (MCF-7/PR) or MCF-7 parental cells were determined by RT-qPCR. Western blotting was conducted to measure the levels of NSD1 protein, apoptosis-associated proteins, Wnt10b protein, H3K36me2 protein, H3K27me3 protein, and signal pathway-associated proteins in MCF-7/PR cells or MCF-7 cells or in vivo subcutaneous xenografted tumor model, and the results demonstrated that NSD1 inhibited cell apoptosis and promoted cell proliferation and tumor growth via activating Wnt/ß-catenin pathway. Cell apoptosis and viability were estimated using cell counting kit-8 assays and flow cytometry. Positive correlation between NSD1 and Wnt10b was identified by chromatin immunoprecipitation assay. The distribution of ß-catenin was determined by immunofluorescence assays. We conclude that NSD1 knockdown inhibits the viability and promotes the apoptosis of paclitaxel-resistant BC cells by inactivating the NSD1/H3K27me3/Wnt10b/ß-catenin signaling pathway.

Characterization of cisplatin-loaded chitosan nanoparticles and rituximab-linked surfaces as target-specific injectable nano-formulations for combating cancer.

The present study was carried out to develop cisplatin-loaded chitosan nanoparticles (CCNP) and cisplatin-loaded chitosan nanoparticle surface linked to rituximab (mAbCCNP) as targeted delivery formulations. The two formulations (CCNP and mAbCCNP) exhibited significant physicochemical properties. The zetapotential (ZP) values of CCNP and mAbCCNP were 30.50 ± 5.64 and 26.90 ± 9.09 mV, respectively; while their particle sizes were 308.10 ± 1.10 and 349.40 ± 3.20 z.d.nm, respectively. The poly dispersity index (PDI) of CCNP was 0.257 ± 0.030 (66.6% PDI), while that of mAbCCNP was 0.444 ± 0.007 (57.60% PDI). Differential scanning calorimetry (DSC) revealed that CCNP had endothermic peaks at temperatures ranging from 135.50 to 157.69 °C. A sharp exothermic peak was observed at 95.79 °C, and an endothermic peak was observed at 166.60 °C. The XRD study on CCNP and mAbCCNP revealed distinct peaks at 2θ. Four peaks at 35.38°, 37.47°, 49.29°, and 59.94° corresponded to CCNP, while three distinct peaks at 36.6°, 49.12°, and 55.08° corresponded to mAbCCNP. The in vitro release of cisplatin from nanoparticles followed zero order kinetics in both CCNP and mAbCCNP. The profile for CCNP showed 43.80% release of cisplatin in 6 h (R2 = 0.9322), indicating linearity of release with minimal deviation. However, the release profile of mAbCCNP showed 22.52% release in 4 h (R2 = 0.9416), indicating linearity with sustained release. In vitro cytotoxicity studies on MCF-7 ATCC human breast cancer cell line showed that CCNP exerted good cytotoxicity, with IC50 of 4.085 ± 0.065 µg/mL. However, mAbCCNP did not elicit any cytotoxic effect. At a dose of 4.00 µg/mL cisplatin induced early apoptosis and late apoptosis, chromatin condensation, while it produced secondary necrosis at a dose of 8.00 µg/mL. Potential delivery system for cisplatin CCNP and mAbCCNP were successfully formulated. The results indicated that CCNP was a more successful formulation than mAbCCNP due to lack of specificity of rituximab against MCF-7 ATCC human breast cancer cells.

G9a Knockdown Suppresses Cancer Aggressiveness by Facilitating Smad Protein Phosphorylation through Increasing BMP5 Expression in Luminal A Type Breast Cancer.

Epigenetic abnormalities affect tumor progression, as well as gene expression and function. Among the diverse epigenetic modulators, the histone methyltransferase G9a has been focused on due to its role in accelerating tumorigenesis and metastasis. Although epigenetic dysregulation is closely related to tumor progression, reports regarding the relationship between G9a and its possible downstream factors regulating breast tumor growth are scarce. Therefore, we aimed to verify the role of G9a and its presumable downstream regulators during malignant progression of breast cancer. G9a-depleted MCF7 and T47D breast cancer cells exhibited suppressed motility, including migration and invasion, and an improved response to ionizing radiation. To identify the possible key factors underlying these effects, microarray analysis was performed, and a TGF-ß superfamily member, BMP5, was selected as a prominent target gene. It was found that BMP5 expression was markedly increased by G9a knockdown. Moreover, reduction in the migration/invasion ability of MCF7 and T47D breast cancer cells was induced by BMP5. Interestingly, a G9a-depletion-mediated increase in BMP5 expression induced the phosphorylation of Smad proteins, which are the intracellular signaling mediators of BMP5. Accordingly, we concluded that the observed antitumor effects may be based on the G9a-depletion-mediated increase in BMP5 expression and the consequent facilitation of Smad protein phosphorylation.

FTY720 in resistant human epidermal growth factor receptor 2-positive breast cancer.

The prognosis of patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer has considerably improved. However, no reliable treatment besides anti-HER2 strategies has been available. FTY720, a small-molecule compound used for treating refractory multiple sclerosis, has been reported to have beneficial effects against cancers. We therefore evaluated the efficacy of FTY720 in trastuzumab-resistant breast cancer cells and investigated the possible mechanism involved. This study evaluated morphological changes after FTY720 treatment. Antiproliferative WST-1 assays and LDH Cytotoxicity Assay Kits were used to determine the treatment effects of drugs, whereas Western blot analysis was used to evaluate protein expression. Apoptotic events were investigated through annexin V staining and TUNEL assays using flow cytometry. FTY720 was effective in trastuzumab-resistant breast cancer cell lines despite the presence of PIK3CA mutation. Studied on a xenograft mouse model, FTY720-treated groups had statistically significantly poorer HCC1954 xenograft growth in vivo compared with the control group. Our findings suggest that FTY720 can overcome resistance to trastuzumab therapy in patients with HER2-positive breast cancer, with FTY720 plus trastuzumab might offer even better efficacy in vitro and in vivo.

Presence of human breast cancer xenograft changes the diurnal profile of amino acids in mice.

Human xenografts are extremely useful models to study the biology of human cancers and the effects of novel potential therapies. Deregulation of metabolism, including changes in amino acids (AAs), is a common characteristic of many human neoplasms. Plasma AAs undergo daily variations, driven by circadian endogenous and exogenous factors. We compared AAs concentration in triple negative breast cancer MDA-MB-231 cells and MCF10A non-tumorigenic immortalized breast epithelial cells. We also measured plasma AAs in mice bearing xenograft MDA-MB-231 and compared their levels with non-tumor-bearing control animals over 24 h. In vitro studies revealed that most of AAs were significantly different in MDA-MB-231 cells when compared with MCF10A. Plasma concentrations of 15 AAs were higher in cancer cells, two were lower and four were observed to shift across 24 h. In the in vivo setting, analysis showed that 12 out of 20 AAs varied significantly between tumor-bearing and non-tumor bearing mice. Noticeably, these metabolites peaked in the dark phase in non-tumor bearing mice, which corresponds to the active time of these animals. Conversely, in tumor-bearing mice, the peak time occurred during the light phase. In the early period of the light phase, these AAs were significantly higher in tumor-bearing animals, yet significantly lower in the middle of the light phase when compared with controls. This pilot study highlights the importance of well controlled experiments in studies involving plasma AAs in human breast cancer xenografts, in addition to emphasizing the need for more precise examination of exometabolomic changes using multiple time points.

Mammary Tumor-Derived Transplants as Breast Cancer Models to Evaluate Tumor-Immune Interactions and Therapeutic Responses.

In breast cancer, the type and distribution of infiltrating immune cells are associated with clinical outcome. Moreover, cancers with abundant tumor-infiltrating lymphocytes (TIL) are more likely to respond to immunotherapy, whereas those in which CD8+ T cells are completely absent (deserts) or excluded are less likely to respond. Detailed understanding of this biology is limited by a lack of preclinical breast cancer models that recapitulate TIL distributions and their associated biology. Here we established mammary tumor-derived transplants (mTDT) from 12 Trp53-null mammary tumors in syngeneic BALB/cJ mice and examined the stability of their growth rate, TIL distribution, and transcriptomic profiles. All mTDTs were estrogen receptor negative. Half of the parental tumors were classified as infiltrated, and the rest were divided between excluded and desert phenotypes. After two orthotopic passages, most (70%) mTDT from infiltrated parents recapitulated this pattern, whereas the desert or excluded parental patterns were maintained in about half of daughter mTDT. Approximately 30% of mTDT gave rise to lung or liver metastases, although metastasis was not associated with a TIL phenotype. Unsupervised transcriptomic analysis clustered mTDT according to their TIL spatial patterns. Infiltrated mTDT transplanted subcutaneously or orthotopically were resistant to anti-PD-L1. Profiling implicated prolonged antigen stimulation and loss of effector function of lymphocytes rather than T-cell exhaustion in the lack of response of infiltrated mTDT to checkpoint blockade. In summary, the molecular diversity and immune complexity of mTDT should facilitate the dissection of mechanisms of breast cancer response to immunotherapies. SIGNIFICANCE: A set of diverse preclinical models of breast cancer is characterized to enable mechanistic dissection of tumor-immune interactions and to improve the efficacy of immunotherapies.