Aggressive Triple-negative Breast Cancer Research Articles

Epidermal growth factor receptor mutations in breast Cancer: Therapeutic challenges and way forward.

Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (RTK) that is upregulated in aggressive triple-negative breast cancer (TNBC). Ligands such as EGF, TGF-α, epigen, and amphiregulin activate the auto-phosphorylation activity of tyrosine residues on EGFR, which regulates the growth, proliferation, adhesion, migration, and survival of cancer cells. Our prior studies depicted that inhibition of EGFR modulates the chemosensitivity in breast cancer stem cells and, thus, serves as a potent therapeutic target in breast cancer. Small-molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs) specifically targeting EGFR have been clinically approved for breast cancer treatment. However, intrinsic and acquired resistance generated due to EGFR mutations limits the applications of designed EGFR-TKIs in breast cancer patients. This review highlights the therapeutic approaches, and the challenges encountered in targeting EGFR-specific mutations. It suggests the need to develop more advanced higher-generation inhibitors for use in combinatorial therapy along with chemo-or-immune therapeutics in clinics as a breast cancer treatment strategy against relapse of the disease.

EXT1 as an Independent Prognostic Biomarker in Breast Cancer: Its Correlation with Immune Infiltration and Clinicopathological Parameters

Exostosin 1 (EXT1) encodes a type II transmembrane glycosyltransferase residing in the endoplasmic reticulum and plays an essential role in the elongation of heparan sulfate chain biosynthesis. Additionally, EXT1 may act as an oncogene that could promote cell proliferation as well as cancer cell metastasis. Herein, we investigated EXT1’s expression pattern and prognostic value in breast cancer, along with its immunological implications. Immunohistochemical staining of EXT1 was assessed in 85 breast cancer patients. Patients were categorized into molecular subtypes, namely luminal A, luminal B, and human epidermal growth factor receptor 2 (HER2), along with triple-negative breast cancer (TNBC). Correlations of EXT1 immunostaining with clinicopathological parameters were evaluated. Furthermore, the correlations of EXT1 expression with tumor immune infiltration and immune cell surface markers were assessed using TIMER. Moreover, survival analysis was conducted to reveal EXT1’s prognostic value. EXT1 expression was markedly associated with the status of the estrogen receptor (ER), molecular subtypes, and recurrence status. In addition, high levels of EXT1 expression were associated with worse overall survival (OS) and relapse-free survival (RFS). Analysis of immune infiltration indicated that EXT1 expression was positively correlated with dendritic cells (DCs), macrophages, neutrophils, CD4+ T cells, and CD8+ T cells, although it showed a negative correlation with the tumor purity. Overall, this study suggests that the elevated EXT1 expression, particularly in TNBC, has a positive correlation with poor prognosis and with immune-infiltrated cells in breast cancer. Therefore, it may emerge as an independent prognostic biomarker, immunological marker, and potential future therapeutic target for the most aggressive TNBC subtype.

The TRIM37 variant rs57141087 contributes to triple-negative breast cancer outcomes in Black women

Triple-negative breast cancer (TNBC) disproportionately affects younger Black women, who show more aggressive phenotypes and poorer outcomes than women of other racial identities. While the impact of socioenvironmental inequities within and beyond health systems is well documented, the genetic influence in TNBC-associated racial disparities remains elusive. Here, we report that cancer-free breast tissue from Black women expresses TRIM37 at a significantly higher level relative to White women. A reporter-based screen for regulatory variants identifies a non-coding risk variant rs57141087 in the 5’ gene upstream region of the TRIM37 locus with enhancer activity. Mechanistically, rs57141087 increases enhancer–promoter interactions through NRF1, resulting in stronger TRIM37 promoter activity. Phenotypically, high TRIM37 levels drive neoplastic transformations in immortalized breast epithelial cells. Finally, context-dependent TRIM37 expression reveals that early-stage TRIM37 levels affect the initiation and trajectory of breast cancer progression. Together, our results indicate a genotype-informed association of oncogenic TRIM37 with TNBC risk in Black women and implicate TRIM37 as a predictive biomarker to better identify patients at risk of aggressive TNBC.

Nanoconjugate Carrying pH-Responsive Transferrin Receptor-Targeted Hesperetin Triggers Triple-Negative Breast Cancer Cell Death through Oxidative Attack and Assemblage of Pro-Apoptotic Proteins.

Triple-negative breast cancer (TNBC) is recognized as a major aggressive subtype of breast cancer due to its expeditious worsening growth, extensive metastatic capability, and recalcitrance to standard current treatments. Hesperetin (HSP), a natural bioflavonoid from citrus fruits, demonstrates pronounced anticancer efficacy, but its hydrophobicity limits its clinical development. The present study reports the fabrication of a biocompatible and pH-responsive transferrin (TF) receptor-targeted HSP-loaded poly(lactic-co-glycolic acid) (PLGA) nanobioconjugate (PLGA-HSP-TF NPs) and the exploration of its in vitro and in vivo antineoplastic potential. PLGA nanoparticles (NPs), PLGA-HSP NPs, and PLGA-HSP-TF NPs were synthesized and characterized by DLS, FTIR, FE-SEM, and 1H NMR spectroscopy. The stability and in vitro release profile of nanoparticles were inspected, and anticancer efficacy was scrutinized in terms of in vitro cytotoxicity, oxidative stress and apoptosis biomarkers, and cell cycle arrest. In vivo tumor regression and host survival studies were executed in Ehrlich ascites carcinoma (EAC) cell-bearing Swiss albino mice. The drug uptake of highly stable PLGA-HSP-TF NPs was accomplished effectively in MDA-MB-231 cells and showed the pH-dependent intracellular release of HSP, which generated excessive intracellular reactive oxygen species (ROS) that led to oxidative assault to the TNBC cells. This elevated ROS dropped the mitochondrial membrane potential and triggered apoptosis-mediated cell death by arresting the cell cycle at the G0/G1 phase. Furthermore, PLGA-HSP-TF NPs unveiled significant in vivo Ehrlich ascites carcinoma regression and host survival compared to free HSP with minimum toxicity at a minimum dose of 20 mg/kg body weight. The study divulges that PLGA-HSP-TF NPs may be an astounding anticancer nanocandidate for aggressive triple-negative breast cancer therapy.

7862 The Paradoxical Role Of ERFFI1 In Breast Cancer Progression Is Supported By Its Dynamic Protein Interactome

Abstract Disclosure: A. Ocampo: None. P.D. Bagamasbad: None. In breast cancer (BCa), glucocorticoid (GC) therapy is used in anti-emetic and palliative care. However, the effects of GC therapy in BCa are conflicting as it is beneficial for hormone-responsive luminal subtypes while it promotes tumor progression in more aggressive triple-negative BCa (TNBCs). A factor implicated in this paradoxical shift is the feedback inhibitor of epidermal growth factor receptor (EGFR) signaling, ERBB receptor feedback inhibitor 1 (ERRFI1). In BCa cell lines, ERRFI1 expression is directly regulated by GC receptor (GR). More interestingly, ERRFI1 was found to restrict the GC-enhanced proliferation in normal breast epithelia but enhances the GC-mediated pro-tumorigenic effects in highly aggressive TNBC. To identify the mechanism behind the shift in ERFFI1 function through BCa progression, ERRFI1 protein interactions in the luminal, HER2, and TNBC subtypes were analyzed by identifying differentially expressed proteins from each subtype using available proteome and interactome datasets from Integrated Interactions Database and followed by network and clustering analyses through STRING. The ERRFI1 interactome varied across the subtypes, and gene ontology analysis of the protein networks revealed progressive tumorigenic effects from the least aggressive luminal subtype to the most aggressive TNBC. The luminal BCa-ERRFI1 interactome showed metastatic potential that is countered by negative regulation of receptor tyrosine kinase (RTK) signaling. The HER2-ERRFI1 interactome highlighted the amplification of RTK signaling and its possible modulation through SRC while the TNBC-ERRFI1 interactome presents pro-oncogenic proteins implicated in drug resistance, angiogenesis, and EMT. Interestingly, the interactome also revealed a link between EGFR signaling and GR signaling possibly through ERRFI1, EGFR, and SFN. To determine the function of ERFFI1 in EGFR signaling in BCa, we generated stable ERRFI1 knockdown in different breast epithelial cell models through lentiviral transduction. Cells were then treated with EGF followed by gene expression analysis of known EGF-upregulated genes such as MYC, GSK3B, MCL1, and MMP9. We found that ERRFI1 knockdown enhanced the EGF-dependent induction of MYC and MMP9 in normal MCF10A cells and this effect was not observed in the TNBC MDA-MB-468 line, suggesting the loss of ERRFI1-mediated inhibition of EGFR signaling with BCa tumorigenic potential. Taken together, our findings suggest that the progressive loss of anti-tumorigenic function of ERRFI1 may be explained by its changing interactome in BCa molecular subtypes. Presentation: 6/3/2024

7862 The Paradoxical Role of ERFFI1 in Breast Cancer Progression Is Supported by Its Dynamic Protein Interactome

Abstract Disclosure: A. Ocampo: None. P.D. Bagamasbad: None. In breast cancer (BCa), glucocorticoid (GC) therapy is used in anti-emetic and palliative care. However, the effects of GC therapy in BCa are conflicting as it is beneficial for hormone-responsive luminal subtypes while it promotes tumor progression in more aggressive triple-negative BCa (TNBCs). A factor implicated in this paradoxical shift is the feedback inhibitor of epidermal growth factor receptor (EGFR) signaling, ERBB receptor feedback inhibitor 1 (ERRFI1). In BCa cell lines, ERRFI1 expression is directly regulated by GC receptor (GR). More interestingly, ERRFI1 was found to restrict the GC-enhanced proliferation in normal breast epithelia but enhances the GC-mediated pro-tumorigenic effects in highly aggressive TNBC. To identify the mechanism behind the shift in ERFFI1 function through BCa progression, ERRFI1 protein interactions in the luminal, HER2, and TNBC subtypes were analyzed by identifying differentially expressed proteins from each subtype using available proteome and interactome datasets from Integrated Interactions Database and followed by network and clustering analyses through STRING. The ERRFI1 interactome varied across the subtypes, and gene ontology analysis of the protein networks revealed progressive tumorigenic effects from the least aggressive luminal subtype to the most aggressive TNBC. The luminal BCa-ERRFI1 interactome showed metastatic potential that is countered by negative regulation of receptor tyrosine kinase (RTK) signaling. The HER2-ERRFI1 interactome highlighted the amplification of RTK signaling and its possible modulation through SRC while the TNBC-ERRFI1 interactome presents pro-oncogenic proteins implicated in drug resistance, angiogenesis, and EMT. Interestingly, the interactome also revealed a link between EGFR signaling and GR signaling possibly through ERRFI1, EGFR, and SFN. To determine the function of ERFFI1 in EGFR signaling in BCa, we generated stable ERRFI1 knockdown in different breast epithelial cell models through lentiviral transduction. Cells were then treated with EGF followed by gene expression analysis of known EGF-upregulated genes such as MYC, GSK3B, MCL1, and MMP9. We found that ERRFI1 knockdown enhanced the EGF-dependent induction of MYC and MMP9 in normal MCF10A cells and this effect was not observed in the TNBC MDA-MB-468 line, suggesting the loss of ERRFI1-mediated inhibition of EGFR signaling with BCa tumorigenic potential. Taken together, our findings suggest that the progressive loss of anti-tumorigenic function of ERRFI1 may be explained by its changing interactome in BCa molecular subtypes. Presentation: 6/3/2024

Antiproliferative Activity of an Organometallic Sn(IV) Coordination Compound Based on 1-Methylbenzotriazole against Human Cancer Cell Lines

A motivating class of compounds with interest in the research field of biological active metallopharmaceuticals for cancer treatment is based on organometallic complexes of Sn(IV), exhibiting advantages such as improved cellular uptake and body excretion, lower toxicity, and fewer side effects compared to platinum-based drugs. In this study, the mononuclear organotin coordination complex [(CH3)2SnCl2(mebta)2] was synthesized and characterized using vibrational spectroscopy (IR, Raman), 1H NMR, 13C{1H} NMR, and X-ray crystallography. Its antiproliferative properties were thoroughly assessed across an aggressive triple-negative human breast cancer cell line. Notably, comparative studies with precursor materials verified that the observed biological activity is intrinsic to the complex itself. This study highlights the compound’s ability to induce cell fate by disrupting essential cellular functions, such as proliferation. By exploring the antiproliferative effects of organotin(IV) derivatives, we introduce a novel class of Sn complexes with 1-methylbenzotriazole (mebta), demonstrating significant potential as promising antitumor agents in the field of organotin compounds.

A SRC-slug-TGFβ2 signaling axis drives poor outcomes in triple-negative breast cancers

SummaryIn our study, we focused on a particular subtype of aggressive breast cancer called Triple-Negative Breast Cancer (TNBC). We investigated a complex series of events that contribute to poor outcomes in this disease and uncovered a crucial signaling cascade driving tumor growth and progression.At the core of this signaling cascade are three key proteins: SRC, AKT, and ERK2. Together, they form a pathway that activates a transcription factor called Slug. Transcription factors act like molecular switches, controlling the expression of genes. Once Slug is activated, it strongly suppresses genes that would normally restrict cell growth and cell spread.One of the genes downregulated by Slug is TGFB2-AS1. This product of the TGFB2-AS1 gene normally controls levels of its target protein called TGF-beta2 (TGFB2), a protein which has roles in cell growth, cell migration and differentiation. Slug downregulation of TGFB2-AS1 results in higher TGFB2 levels, and this in turn contributes to the uncontrolled growth and spread of cancer cells. TGFB2, and other proteins in this pathway (SRC, AKT, ERK2, and a Slug interactor called LSD1) all maintain the stability of Slug, meaning that Slug levels remain high and drive the aggressive features of this subtype of breast cancer.Overall, our research sheds light on the intricate molecular mechanisms driving aggressive TNBC. It also identifies potential targets for future therapies, aimed at disrupting this harmful signaling pathway and potentially improving patient outcomes for this disease.

Discovering the potential of biomaterial-based mesoporous and magneto-luminescent nanohybrid (Nd-doped Hydroxyapatite/Fe3O4) for cancer theragnosis

Multimodality nanoplatforms play a crucial role in advancing medical interventions by integrating multiple functionalities into a single system. However, issues like intricate production processes and biocompatibility persist. Herein, a facile synthesis of a biomaterial-based mesoporous nanocarrier, HAp:Nd+SPIONs@mSiO2 is reported. The nanohybrid with ∼100 nm average size, comprised of Nd-doped hydroxyapatite (HAp:Nd) nanophosphor, Fe3O4 superparamagnetic iron oxide nanoparticles (SPIONs), and mesoporous silica, exhibiting magneto-luminescent properties. The nanohybrid showed NIR to NIR photoluminescence properties important for deep tissue imaging. The mesoporous nanohybrid was loaded with Indocyanine green (ICG), a photosensitizer and photothermal dye, as a model drug (∼6 μg/mg of nanoparticles) with a high absorption stability retaining >75 % drug until 24 h incubation in pH 6 and 7.4, respectively. Nanoparticles demonstrated dual functionality by generating heat through magnetic and photonic stimulation, as well as producing reactive oxygen species (ROS) upon excitation with 808 nm light. In vitro assays on aggressive triple-negative breast cancer cells (MDA-MB-231) showed the high biocompatibility of nanohybrid with and without ICG, while a significant toxicity was seen after irradiation of NIR light due to ROS production. Noticeably, the nanohybrids also exhibit the ability to monitor temperature changes via Nd3+ associated NIR luminescence. The nanoplatform integrates clinically relevant components like hydroxyapatite, SPIONs, mesoporous silica and ICG, highlighting its potential for translational applications. The developed nanohybrids, with combined NIR-mediated photothermal and photodynamic effects, magnetic photothermal capabilities, and NIR/MR imaging, offer promise in addressing cancer heterogeneity and improving conventional treatments with reduced side effects.

Autophagy Deficiency Induced by SAT1 Potentiates Tumor Progression in Triple-Negative Breast Cancer.

Aggressive triple-negative breast cancer (TNBC) still lacks approved targeted therapies, requiring more exploration of its underlying mechanisms. Previous studies have suggested a potential role of SAT1 (Spermidine/Spermine N1-acetyltransferase 1) in cancer, which needs to be further elucidated in breast cancer. In this study, highly expressed SAT1 in TNBC signified worse patient prognoses. And SAT1 knockdown effectively inhibited the proliferation and migration abilities of TNBC cells in vitro and in vivo. In terms of mechanism, the transcription factor JUN enhanced SAT1 transcriptional activity by binding to its promoter region. Then, SAT1 protein in the cytoplasm engaged in directly binding with YBX1 for sustaining YBX1 protein stability via deubiquitylation mediated by the E3 ligase HERC5. Further, SAT1 was found to suppress autophagy remarkably via stabilization of mTOR mRNA with the accumulation of YBX1-mediated methyl-5-cytosine (m5C) modification. These findings proved that SAT1 drives TNBC progression through the SAT1/YBX1/mTOR axis, which may provide a potential candidate for targeted therapy in advanced TNBC.

19F MRI/CEUS Dual Imaging-Guided Sonodynamic Therapy Enhances Immune Checkpoint Blockade in Triple-Negative Breast Cancer.

Treatment of highly aggressive triple-negative breast cancer (TNBC) in the clinic is challenging. Here, a liposome nanodrug (LP@PFH@HMME) integrating imaging agents and therapeutic agents for bimodal imaging-guided sonodynamic therapy (SDT) is developed, which boosted immunogenicity to enable potent immunotherapy via immune checkpoint blockade (ICB) in TNBC. In the acidic tumor microenvironment (TME), LP@PFH@HMME undergoes "nano-to-micro" transformation due to a pH-responsive lipid fusion, which makes droplets much more sensitive to ultrasound (US) in contrast-enhanced ultrasound (CEUS) and SDT studies. The nanodrug demonstrates robust bimodal imaging ability through fluorine-19 magnetic resonance imaging (19F MRI) and CEUS bimodal imaging, and it exhibits excellent solubility in aqueous solution with relatively high 19F content and desirable long transverse relaxation time (T2 = 1.072 s), making it suitable for high-performance 19F MRI, in addition to effective accumulation of nanodrugs after tail vein injection. Thus, 19F MRI/CEUS dual imaging is achievable to show adequate time points for US irradiation of tumor sites to induce highly effective SDT, which produces abundant reactive oxygen species (ROS) triggering immunogenic cell death (ICD) to assist ICB-based immunotherapy. The combination treatment design of sonodynamic therapy with immunotherapy effectively inhibited TNBC growth and recurrence, highlighting the promise of multifunctional nanodrugs in treating TNBC.

The GPR30 Receptor Is Involved in IL-6-Induced Metastatic Properties of MCF-7 Luminal Breast Cancer Cells.

Luminal breast cancer has a high incidence worldwide and poses a severe health threat. Estrogen receptor alpha (ER-α) is activated by 17β-estradiol (E2), and its overexpression promotes cancerous characteristics. Luminal breast cancer is an epithelial type; however, the cytokine IL-6, secreted by cells within the tumor microenvironment, stimulates the epithelial-to-mesenchymal transition (EMT) and promotes metastasis. Also, IL-6 decreases ER-α levels, favoring the tamoxifen (TMX) resistance development. However, genes under E2 regulation continue to be expressed even though this receptor is absent. GPR30 is an alternative E2 receptor present in both luminal and aggressive triple-negative breast cancer and is related to TMX resistance and cancer progression. The roles of GPR30 and IL-6 in metastasis have been individually established; however, their interplay remains unexplored. This study aims to elucidate the role of GPR30 in IL-6-induced metastatic properties of MCF-7 luminal breast cancer cells. Results showed that GPR30 contributes to the E2-induced MCF-7 proliferation because its inhibition with the antagonist G15 and the Pertussis toxin (PTX) reduced it. Besides, GPR30 upregulated vimentin and downregulated E-cadherin levels in MCF-7 and TMX-resistant (R-TMX) cells and is also involved in the IL-6-induced migration, invasion, and TMX resistance in MCF-7 cells. In addition, in MDA-MB-231 triple-negative cells, both basal and IL-6-induced metastatic properties were related to GPR30 activity. These results indicate that the GPR30 receptor regulates the EMT induced by IL-6 in breast cancer cells.

Density Gradient Centrifugation Is an Effective Tool to Isolate Cancer Stem-like Cells from Hypoxic and Normoxia Triple-Negative Breast Cancer Models.

Accumulating evidence has indicated that stemness-related genes are associated with the aggressiveness of triple-negative breast cancer (TNBC). Because no universal markers for breast CSCs are available, we applied the density gradient centrifugation method to enrich breast CSCs. We demonstrated that the density centrifugation method allows for the isolation of cancer stem cells (CSCs) from adherent and non-adherent MCF7 (Luminal A), MDA-MB-231 (TNBC) and MDA-MB-468 (TNBC) breast cancer cells. The current study shows that the CSCs' enriched fraction from Luminal A and TNBC cells have an increased capacity to grow anchorage-independently. CSCs from adherent TNBC are mainly characterized by metabolic plasticity, whereas CSCs from Luminal A have an increased mitochondrial capacity. Moreover, we found that non-adherent growth CSCs isolated from large mammospheres have a higher ability to grow anchorage-independently compared to CSCs isolated from small mammospheres. In CSCs, a metabolic shift towards glycolysis was observed due to the hypoxic environment of the large mammosphere. Using a bioinformatic analysis, we indicate that hypoxia HYOU1 gene overexpression is associated with the aggressiveness, metastasis and poor prognosis of TNBC. An in vitro study demonstrated that HYOU1 overexpression increases breast cancer cells' stemness and hyperactivates their metabolic activity. In conclusion, we show that density gradient centrifugation is a non-marker-based approach to isolate metabolically flexible (normoxia) CSCs and glycolytic (hypoxic) CSCs from aggressive TNBC.

FTY720/Fingolimod mitigates paclitaxel-induced Sparcl1-driven neuropathic pain and breast cancer progression.

Paclitaxel is among the most active chemotherapy drugs for the aggressive triple negative breast cancer (TNBC). Unfortunately, it often induces painful peripheral neuropathy (CIPN), a major debilitating side effect. Here we demonstrate that in naive and breast tumor-bearing immunocompetent mice, a clinically relevant dose of FTY720/Fingolimod that targets sphingosine-1-phosphate receptor 1 (S1PR1), alleviated paclitaxel-induced neuropathic pain. FTY720 also significantly attenuated paclitaxel-stimulated glial fibrillary acidic protein (GFAP), a marker for activated astrocytes, and expression of the astrocyte-secreted synaptogenic protein Sparcl1/Hevin, a key regulator of synapse formation. Notably, the formation of excitatory synapses containing VGluT2 in the spinal cord dorsal horn induced by paclitaxel was also inhibited by FTY720 treatment, supporting the involvement of astrocytes and Sparcl1 in CIPN. Furthermore, in this TNBC mouse model that mimics human breast cancer, FTY720 administration also enhanced the anti-tumor effects of paclitaxel, leading to reduced tumor progression and lung metastasis. Taken together, our findings suggest that targeting the S1P/S1PR1 axis with FTY720 is a multipronged approach that holds promise as a therapeutic strategy for alleviating both CIPN and enhancing the efficacy of chemotherapy in TNBC treatment.

Identification of Poliovirus Receptor-like 3 Protein as a Prognostic Factor in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) represents an aggressive subtype of breast cancer, with a bad prognosis and lack of targeted therapeutic options. Characterized by the absence of estrogen receptors, progesterone receptors, and HER2 expression, TNBC is often associated with a significantly lower survival rate compared to other breast cancer subtypes. Our study aimed to explore the prognostic significance of 83 immune-related genes, by using transcriptomic data from the TCGA database. Our analysis identified the Poliovirus Receptor-Like 3 protein (PVRL3) as a critical negative prognostic marker in TNBC patients. Furthermore, we found that the Enhancer of Zeste Homolog 2 (EZH2), a well-known epigenetic regulator, plays a pivotal role in modulating PVRL3 levels in TNBC cancer cell lines expressing EZH2 along with high levels of PVRL3. The elucidation of the EZH2-PVRL3 regulatory axis provides valuable insights into the molecular mechanisms underlying TNBC aggressiveness and opens up potential pathways for personalized therapeutic intervention.

Reducing Breast Cancer Disparities with Precision Public Health: A New Strategy to Improve Prevention and Advance Health Equity in Delaware Hotspots.

While Black and White women are diagnosed with breast cancer (BC) at similar rates, Black women die from BC at a 40% higher rate. This disparity is even more pronounced for younger Black women, who die from BC at nearly twice the rate as younger White women. Black-White differences in BC mortality are largely attributable to health care and tumor biology factors. Black women face greater barriers to accessing BC screening and are twice as likely to be diagnosed with the aggressive triple-negative breast cancer (TNBC) subtype. Delaware leads the US for the incidence of late-stage BC diagnosed among younger women and TNBC. This commentary begins with a discussion of precision public health, an emerging framework that builds on and complements recent advances in precision medicine. Next, a new precision public health initiative designed to reduce BC disparities in Delaware by targeting local hotspots with prevention interventions is presented. Finally, next steps are considered for implementation, evaluation, and new research activities.

The intricate relationship between obesity, type 2 diabetes and female breast cancer: A retrospective study of 335 women.

Type 2 diabetes (T2D) is a risk factor for female breast cancer (FBC). Obesity has also been associated with FBC, also depending on menopausal status. This study aimed to evaluate the impact of obesity and T2D on the development, aggressiveness, and invasiveness of FBC. Demographic, clinical, and histopathological data from 335 women with FBC were collected, and analyzed according to weight category (102 normal weight, 117 overweight, and 116 living with obesity) and the presence/absence of T2D. Age at oncologic diagnosis was not statistically significantly different for body weight; women with overweight or obesity were more likely to have an oncologic diagnosis after menopause than normal weight (p<0.001). The presence of overweight/obesity and T2D seemed to be associated with a higher incidence of metastasis, recurrence, and triple-negative breast cancer (TNBC) subtype (p<0.001). Excess body weight was also associated with high histologic grade (G3) (p<0.005). These results confirm excess body weight and T2D as unfavorable prognostic factors in terms of the presence of the TNBC subtype, tumor metastasis, recurrence, and aggressiveness (G3 and Ki-67>20%). This study highlights the importance of prevention in all women, with early screening, and adequate nutritional programs.

Synthetic Benzylic Diselenides and Disulfides: Potential Anticancer Activities via Modulation of the ROS-dependent Akt/β-Catenin Signaling Pathway.

The natural and synthetic organodiselenides have garnered much research attention due to their chemotherapeutic and chemopreventive activities. Herein, we describe the synthesis of a series of benzylic diselenides, which were synthesized by coupling the in situ generated disodium diselenide with the corresponding benzylic halides. The diselenides were evaluated for their anticancer activities in the highly aggressive triple-negative breast cancer cells. Preliminary anti-proliferative activities indicated 4-cyano-substituted diselenide 7 to be most potent with an IC50 value of 1.9 ± 0.3 μM. Detailed mechanistic investigations showed that diselenide 7 induces apoptosis and causes G1 phase arrest of the cell cycle. It exhibits anticancer activity by suppressing the Akt/β-catenin signaling pathway. Further control experiments with LiCl (inhibitor of GSK-3β) revealed that down-regulation of β-catenin was promoted by GSK-3β-induced phosphorylation of β-catenin and its subsequent proteasomal degradation. Moreover, the intracellular ROS was found to act as an upstream mediator for the inactivation of the Akt/β-catenin signaling pathway. The present study describing the efficient anticancer activity of a synthetic benzylic diselenide towards triple-negative breast cancer cells through the modulation of ROS-dependent Akt/β-catenin signaling pathway would certainly be helpful in the future towards the development of small-molecule organoselenium compounds for the treatment of cancer.

Elucidating the nature of acinic cell carcinoma of the breast with high-grade morphology: evidence from case report

BackgroundAcinic cell carcinoma (AciCC) of the breast is a rare subtype of breast cancer. It was considered a low-grade triple-negative breast cancer (TNBC) with the potential to progress or transform into a high-grade lesion because of the molecular similarities with conventional aggressive TNBC in several genetic studies. Microscopically, the coexistence of classical low-grade and high-grade triple-negative components in breast AciCC is not uncommon. However, there is a scarcity of research on the comparative histopathological and genetic aspects of both components.Case presentationA 34-year-old woman with a nontender mass in the upper outer quadrant of the left breast was initially diagnosed with a malignant small round cell tumor (undifferentiated or poorly differentiated carcinoma) based on a preoperative biopsy, which was later identified as breast AciCC with a high-grade solid component. Left breast-conserving surgery with sentinel lymph node biopsy was performed. Microscopically, the breast AciCC consisted of a classical acinic component and a high-grade component. The latter demonstrated a solid sheet-like pattern characterized by large, round, pleomorphic or vesicular nuclei, prominent nucleoli, and frequent mitotic activities. Classical acinic architectures focally merged together to form solid nests and transited into high-grade areas. Remarkably, in the high-grade lesion, conventional immunochemical markers for breast AciCC, such as α1-antitrypsin (AAT), Lysozyme (LYS), Epithelial membrane antigen (EMA), S100 protein (S100), and cytokeratin (CK) were negative, whereas cell cycle protein D1 (cyclin D1) and vimentin showed diffuse expression. Next‑generation sequencing (NGS) revealed that 43.5% of variants were identical in both components. Furthermore, PAK5 mutation; copy number (CN) loss of CDH1, CHEK1, and MLH1; and CN gains of CDK6, HGF, and FOXP1 were identified in the high-grade lesion. The patient was treated with eight cycles of adjuvant chemotherapy (epirubicin combined with cyclophosphamide) and radiotherapy after surgery, and she is currently alive for 43 months with no metastases or recurrences.ConclusionsThis case demonstrates a comparative analysis of the histopathological and genetic characteristics of classical low-grade and high-grade components of AciCC within the same breast. This information may serve as a morphological and molecular basis for further investigation into the molecular mechanisms underlying high-grade lesions in breast AciCC.

MAZ-mediated up-regulation of BCKDK reprograms glucose metabolism and promotes growth by regulating glucose-6-phosphate dehydrogenase stability in triple-negative breast cancer

Tumour metabolic reprogramming is pivotal for tumour survival and proliferation. Investigating potential molecular mechanisms within the heterogeneous and clinically aggressive triple-negative breast cancer (TNBC) subtype is essential to identifying novel therapeutic targets. Accordingly, we investigated the role of branched-chain α-keto acid dehydrogenase kinase (BCKDK) in promoting tumorigenesis in TNBC. We analysed The Cancer Genome Atlas dataset and immunohistochemically stained surgical specimens to investigate BCKDK expression and its prognostic implications in TNBC. The effects of BCKDK on tumorigenesis were assessed using cell viability, colony formation, apoptosis, and cell cycle assays, and subsequently validated in vivo. Metabolomic screening was performed via isotope tracer studies. The downstream target was confirmed using mass spectrometry and a co-immunoprecipitation experiment coupled with immunofluorescence analysis. Upstream transcription factors were also examined using chromatin immunoprecipitation and luciferase assays. BCKDK was upregulated in TNBC tumour tissues and associated with poor prognosis. BCKDK depletion led to reduced cell proliferation both in vitro and vivo. MYC-associated zinc finger protein (MAZ) was confirmed as the major transcription factor directly regulating BCKDK expression in TNBC. Mechanistically, BCKDK interacted with glucose-6-phosphate dehydrogenase (G6PD), leading to increased flux in the pentose phosphate pathway for macromolecule synthesis and detoxification of reactive oxygen species. Forced expression of G6PD rescued the growth defect in BCKDK-deficient cells. Notably, the small-molecule inhibitor of BCKDK, 3,6-dichlorobenzo(b)thiophene-2-carboxylic acid, exhibited anti-tumour effects in a patient-derived tumour xenograft model. Our findings hold significant promise for developing targeted therapies aimed at disrupting the MAZ/BCKDK/G6PD signalling pathway, offering potential advancements in treating TNBC through metabolic reprogramming.