Target For Breast Cancer Therapy Research Articles

Hsa_circ_0137652 Regulates miR-1205/CCNB1 Axis to Accelerate the Malignancy of Breast Cancer.

CircRNAs have become a hotspot in tumor research owing to their high stability and specific functions. We investigated the function of hsa_circ_0137652 in the onset and progression of breast cancer (BC). The expression of circ_0137652, miR-1205, and CCNB1 in BC tissues and cell lines were detected using RT-qPCR and/or western blotting. Dual-luciferase reporter and RNA immunoprecipitation chip assays were used to confirm any potential connections between circ_0137652, miR-1205, and CCNB1. CCK-8 and clone formation assays (CFA)were used to measure the proliferation of BC cells. The Transwell assay was used to investigate the migration of BC cells, and the impact of circ_0137652 on BC tumor formation in vivo was validated using animal experiments. RT-qPCR results showed that circ_0137652 and CCNB1 in breast cancer tissues were notably upregulated in normal tissues, whereas miR-1205 was prominently downregulated. After silencing circ_0137652, the growth and migration of BC cells were reduced. Animal experiments showed that circ_0137652 hampers the tumorigenesis of BC cells in vivo. Additionally, we found that circ_0137652 functions as a sponge for miR-1205. Moreover, the miR-1205 inhibitor notably facilitated cell proliferation and migration and attenuated the action of circ_0137652 knockdown. Furthermore, miR-1205 inhibits BC progression by targeting CCNB1. Circ_0137652 controls the miR-1205/CCNB1 axis to induce increased breast cancer malignancy. Our findings suggest that circ_0137652 may be a novel target for BC therapy.

Cancer-Associated Adipocytes and Breast Cancer: Intertwining in the Tumor Microenvironment and Challenges for Cancer Therapy.

Adipocytes are the main components in breast tissue, and cancer-associated adipocytes (CAAs) are one of the most important components in the tumor microenvironment of breast cancer (BC). Bidirectional regulation was found between CAAs and BC cells. BC facilitates the dedifferentiation of adjacent adipocytes to form CAAs with morphological and biological changes. CAAs increase the secretion of multiple cytokines and adipokines to promote the tumorigenesis, progression, and metastasis of BC by remodeling the extracellular matrix, changing aromatase expression, and metabolic reprogramming, and shaping the tumor immune microenvironment. CAAs are also associated with the therapeutic response of BC and provide potential targets in BC therapy. The present review provides a comprehensive description of the crosstalk between CAAs and BC and discusses the potential strategies to target CAAs to overcome BC treatment resistance.

LINC01140 Hinders the Development of Breast Cancer Through Targeting miR-200b-3p to Downregulate DMD

Long non-coding RNAs (lncRNAs) are frequently reported to be involved in breast cancer (BC) oncogenicity. The goal of this study was to probe lncRNA LINC01140’s role and action mechanism in BC. Relative LINC01140, miR-200b-3p, and dystrophin (DMD) levels were determined using quantitative real-time polymerase chain reaction (qRT-PCR). DMD protein levels in BC cells were quantified using Western blotting, and the targeting relationships were validated by luciferase reporter assays and RNA immunoprecipitation experiments. The proliferative potential of the cells was evaluated using CCK-8 and colony formation tests, while the migratory and invasive abilities of the cells were assessed using scratch and transwell assays. Apoptosis was assessed by flow cytometry. Nude mouse models have been established to allow the examination of tumor growth in vivo. Pronounced downregulation of LINC01140 and DMD, as well as upregulation of miR-200b-3p, was observed in BC. LINC01140 binds directly to miR-200b-3p to downregulate DMD expression. Ectopic LINC01140 expression not only limited tumor growth in vivo but also diminished the proliferation, migration, and invasion abilities of BC cells in vitro, however, it induced apoptosis in BC cells. Elevated miR-200b-3p expression stimulated the tumorigenic potential of BC cells and attenuated the suppressive effect of LINC01140 or DMD overexpression on BC cell malignancy, whereas DMD overexpression restricted the tumorigenic potential of BC cells. Overall, LINC01140 prevents BC development via the miR-200b-3p–DMD axis. These findings support the latent potential and usefulness of the LINC01140-miR-200b-3p–DMD network as a target for BC therapy.

The delta subunit of the GABAA receptor is necessary for the GPT2-promoted breast cancer metastasis.

Objectives: Glutamic pyruvate transaminase (GPT2) catalyzes the reversible transamination between alanine and α-ketoglutarate (α-KG) to generate pyruvate and glutamate during cellular glutamine catabolism. The glutamate could be further converted to γ-aminobutyric acid (GABA). However, the role of GPT2 in tumor metastasis remains unclear. Methods: The wound healing and transwell assays were carried out to analyze breast cancer cell migration and invasion in vitro. Gene ontology analysis was utilized following RNA-sequencing to discover the associated molecule function. The mass spectrometry analysis following phosphoprotein enrichment was performed to discover the associated transcription factors. Most importantly, both the tail vein model and Mammary gland conditional Gpt2-/- spontaneous tumor mouse models were used to evaluate the effect of GPT2 on breast cancer metastasis in vivo. Results: GPT2 overexpression increases the content of GABA and promotes breast cancer metastasis by activating GABAA receptors. The delta subunit GABRD is necessary for the GPT2/GABA-induced breast cancer metastasis in xenograft and transgenic mouse models. Gpt2 knockout reduces the lung metastasis of the genetic Gpt2-/- breast cancer in mice and prolongs the overall survival of tumor burden mice. Mechanistically, GPT2-induced GABAA receptor activation increases Ca2+ influx by turning on its associated calcium channel, and the surged intracellular calcium triggers the PKC-CREB pathway activation. The activated transcription factor CREB accelerates breast cancer metastasis by upregulating metastasis-related gene expressions, such as PODXL, MMP3, and MMP9. Conclusion: In summary, this study demonstrates that GPT2 promotes breast cancer metastasis through up-regulated GABA activation of GABAAR-PKC-CREB signaling, suggesting it is a potential target for breast cancer therapy.

GSH-activatable camptothecin prodrug-loaded gold nanostars coated with hyaluronic acid for targeted breast cancer therapy via multiple radiosensitization strategies.

Breast cancer has overtaken lung cancer to rank as the top malignant tumor in terms of incidence. Herein, a gold nanostar (denoted as AuNS) is used for loading disulfide-coupled camptothecin-fluorophore prodrugs (denoted as CPT-SS-FL) to form a nanocomposite of AuNS@CPT-SS-FL (denoted as AS), which, in turn, is further encapsulated with hyaluronic acid (HA) to give the final nanoplatform of AuNS@CPT-SS-FL@HA (denoted as ASH). ASH effectively carries the prodrug and targets the CD44 receptor on the surface of tumor cells. The endogenously overexpressed glutathione (GSH) in tumor cells breaks the disulfide bond to activate the prodrug and release the radiosensitizer drug camptothecin (CPT) and the fluorescence imaging reagent rhodamine derivative as a fluorophore (FL). The released FL can track the precise release position of the radiosensitizer camptothecin in tumor cells in real time. The AuNS has strong X-ray absorption and deposition ability due to the high atomic coefficient of elemental Au (Z = 79). At the same time, the AuNS can alleviate the tumor microenvironment (TME) hypoxia through its mild photothermal therapy (PTT). Therefore, through the multiple radiosensitizing effects of GSH depletion, the high atomic coefficient of Au, and hypoxia alleviation, accompanied by the radiosensitizer camptothecin, the designed ASH nanoplatform can effectively induce strong immunogenic cell death (ICD) at the tumor site via radiosensitizing therapy combined with PTT. This work provides a new way of constructing a structurally compact and highly functionalized hierarchical system toward efficient breast cancer treatment through ameliorating the TME with multiple modalities.

Functionalized manganese iron oxide nanoparticles: a dual potential magneto-chemotherapeutic cargo in a 3D breast cancer model.

Localized heat generation from manganese iron oxide nanoparticles (MIONPs) conjugated with chemotherapeutics under the exposure of an alternating magnetic field (magneto-chemotherapy) can revolutionize targeted breast cancer therapy. On the other hand, the lack of precise control of local temperature and adequate MIONP distribution in laboratory settings using the conventional two-dimensional (2D) cellular models has limited its further translation in tumor sites. Our current study explored advanced 3D in vitro tumor models as a promising alternative to replicate the complete range of tumor characteristics. Specifically, we have focused on investigating the effectiveness of MIONP-based magneto-chemotherapy (MCT) as an anticancer treatment in a 3D breast cancer model. To achieve this, chitosan-coated MIONPs (CS-MIONPs) are synthesized and functionalized with an anticancer drug (doxorubicin) and a tumor-targeting aptamer (AS1411). CS-MIONPs with a crystallite size of 16.88 nm and a specific absorption rate (SAR) of 181.48 W g-1 are reported. In vitro assessment of MCF-7 breast cancer cell lines in 2D and 3D cell cultures demonstrated anticancer activity. In the 2D and 3D cancer models, the MIONP-mediated MCT reduced cancer cell viability to about 71.48% and 92.2%, respectively. On the other hand, MIONP-mediated MCT under an AC magnetic field diminished spheroids' viability to 83.76 ± 2%, being the most promising therapeutic modality against breast cancer.

Epidermal growth factor receptor targeted doxorubicin and vitexin loaded niosomes for enhanced breast cancer therapy

NIODVC (cetuximab-conjugated doxorubicin and vitexin loaded niosome) proves effective for targeted breast cancer therapy. Enhanced cytotoxicity, cellular uptake, and gene downregulation show promise.

Doxorubicin-loaded polymeric micelles decorated with nitrogen-doped carbon dots for targeted breast cancer therapy

A pH-tunable “on-off” module polymeric micelles (PM) composed of two parts, a hydrophilic (polyethylene glycol) shell and a hydrophobic (resorcinol) core, was synthesized. Doxorubicin (DOX) was encapsulated into the micelle core via hydrophobic interaction. Due to the low toxicity, good fluorescence emission, water solubility, and biocompatibility, nitrogen-doped carbon quantum dots (NCDs) were used as labels to form PMs with robust fluorescence characteristics. NCDs were synthesized (particle size of 2.26 nm and fluorescence quantum yield of 8.2%). The prepared PM with 28 nm in size demonstrated desirable DOX-loading content of 33.64% and encapsulation efficiency of 48.90%. Analyses such as FT-IR, dynamic light scattering, and transmission electron microscopy were used to determine the characteristics of prepared fluorescence drug-loaded micelles (NCD@DOX/PM). The developed nanocarrier revealed a sustained release profile where 94.0% of the encapsulated DOX was released within 24 h in pH 5.0. Moreover, the in vitro cytotoxicity test of NCD@DOX/PM showed about 30% cell viability on MCF-7 cells at the maximum dose of 4.5 μg/mL. Overall, all these appealing attributes make micelles a promising modality for the delivery and controlled release of DOX in tumor cells.

WW domain binding protein 2 (WBP2) as an oncogene in breast cancer: mechanisms and therapeutic prospects-a narrative review.

WW domain binding protein 2 (WBP2), considered an emerging breast cancer gene, functions as a binding partner for WW domain proteins. The WBP2 gene is involved in mediating the malignant development and clinical drug resistance of breast cancer, but its potential mechanism remains unclear. Therefore, it is necessary to elucidate the mechanism of WBP2 in breast cancer, which will help to provide new methods for clinical diagnosis and treatment of breast cancer. The PubMed database was searched using the terms "WW Domain Binding Protein 2" or "WBP2", "breast cancer" or "breast neoplasms" or "human cancer" from January 1997 through August 2022. Through the screening and evaluation of titles and abstracts, about 120 English articles were included in this study. By describing the multiple regulatory functions of WBP2 at the transcriptional, post-transcriptional, and post-translational levels, and summarizing how WBP2 as a key node crosstalks multiple signaling pathways, we reveal the ability of WBP2 to promote breast cancer malignant progression. In different subtypes of breast cancer, the mechanism of WBP2-mediated drug resistance is related to estrogen receptor and epidermal growth factor receptor (EGFR) 2 status, and hormones may be an essential factor in WBP2-mediated drug resistance. In addition, we discuss the application prospects of WBP2 in targeted therapy and immunotherapy and propose therapeutic strategies to overcome drug resistance in breast cancer by jointly targeting WBP2 and its related molecules. This provides a theoretical basis for the innovation of breast cancer targeted drugs. WBP2 is a promising target for breast cancer therapy. Nuclear WBP2, as the main functional form of WBP2 after its activation, is a meaningful indicator for the diagnosis and prediction of breast cancer progression.

BPTF promotes the progression of distinct subtypes of breast cancer and is a therapeutic target.

To assess the biomarker and functional role of the chromatin remodeling factor, bromodomain PHD finger transcription factor (BPTF), in breast cancer progression. BPTF copy number was assessed using fluorescence in situ hybridization. BPTF expression was regulated in breast cancer cells by shRNA/siRNA-mediated gene silencing and BPTF cDNA overexpression. The effects of regulating BPTF expression were examined on key oncogenic signaling pathways and on breast cancer cell proliferation, apoptosis, and cell cycle progression, as well as in xenograft models. The consequences of pharmacological bromodomain inhibition, alone or in combination with other targeted agents, on breast cancer progression were assessed in culture and in xenograft models. BPTF copy number was gained in 34.1% and separately amplified in 8.2% of a breast cancer tissue cohort. Elevated BPTF copy number was significantly associated with increasing patient age and tumor grade and observed in both ER-positive and triple-negative breast cancer (TNBC) subtypes. BPTF copy number gain and amplification were also observed in The Cancer Genome Atlas (TCGA) breast cancer cohort. Stable shRNA-mediated silencing of BPTF significantly inhibited cell proliferation and induced apoptosis in TNBC and ER-positive human breast cancer cell lines. BPTF knockdown suppressed signaling through the phosphoinositide 3 kinase (PI3K) pathway, including reduced expression of phosphorylated AKT (Ser473), phosphorylated GSK-β (Ser9), and CCND1. These findings were confirmed following transient BPTF knockdown by a distinct siRNA in TNBC and ER-positive breast cancer cells. Stable suppression of BPTF expression significantly inhibited the in vivo growth of TNBC cells. Conversely, BPTF cDNA overexpression in TNBC and ER-positive breast cancer cells enhanced breast cancer cell proliferation and reduced apoptosis. BPTF targeting with the bromodomain inhibitor bromosporine, alone or in combination with the PI3K pathway inhibitor gedatolisib, produced significant anti-tumor effects against TNBC cells in vitro and in vivo. These studies demonstrate BPTF activation in distinct breast cancer subtypes, identify pathways by which BPTF promotes breast cancer progression, and suggest BPTF as a rational target for breast cancer therapy.

Advances in Aptamers-Based Applications in Breast Cancer: Drug Delivery, Therapeutics, and Diagnostics.

Aptamers are synthetic single-stranded oligonucleotides (such as RNA and DNA) evolved in vitro using Systematic Evolution of Ligands through Exponential enrichment (SELEX) techniques. Aptamers are evolved to have high affinity and specificity to targets; hence, they have a great potential for use in therapeutics as delivery agents and/or in treatment strategies. Aptamers can be chemically synthesized and modified in a cost-effective manner and are easy to hybridize to a variety of nano-particles and other agents which has paved a way for targeted therapy and diagnostics applications such as in breast tumors. In this review, we systematically explain different aptamer adoption approaches to therapeutic or diagnostic uses when addressing breast tumors. We summarize the current therapeutic techniques to address breast tumors including aptamer-base approaches. We discuss the next aptamer-based therapeutic and diagnostic approaches targeting breast tumors. Finally, we provide a perspective on the future of aptamer-based sensors for breast therapeutics and diagnostics. In this section, the therapeutic applications of aptamers will be discussed for the targeting therapy of breast cancer.

Immunotherapy against the Cystine/Glutamate Antiporter xCT Improves the Efficacy of APR-246 in Preclinical Breast Cancer Models.

Breast cancer is the most frequent cancer in women. Despite recent clinical advances, new therapeutic approaches are still required. The cystine-glutamate antiporter xCT, encoded by the SLC7A11 gene, which imports cystine in exchange with glutamate, is a potentially new target for breast cancer therapy, being involved in tumor cell redox balance and resistance to therapies. xCT expression is regulated by the oncosuppressor p53, which is mutated in many breast cancers. Indeed, mutant p53 (mut-p53) can induce xCT post-transcriptional down modulation, rendering mut-p53 tumors susceptible to oxidative damage. Interestingly, the drug APR-246, developed to restore the wild-type function of p53 in tumors harboring its mutation, alters the cell redox balance in a p53-independent way, possibly rendering the cells more sensitive to xCT inhibition. Here, we propose a combinatorial treatment based on xCT immunetargeting and APR-246 treatment as a strategy for tackling breast cancer. We demonstrate that combining the inhibition of xCT with the APR-246 drug significantly decreased breast cancer cell viability in vitro and induced apoptosis and affected cancer stem cells' self-renewal compared to the single treatments. Moreover, the immunetargeting of xCT through DNA vaccination in combination with APR-246 treatment synergistically hinders tumor progression and prevents lung metastasis formation in vivo. These effects can be mediated by the production of anti-xCT antibodies that are able to induce the antibody dependent cellular cytotoxicity of tumor cells. Overall, we demonstrate that DNA vaccination against xCT can synergize with APR-246 treatment and enhance its therapeutic effect. Thus, APR-246 treatment in combination with xCT immunetargeting may open new perspectives in the management of breast cancer.

A preliminary study to establish the transfected CHO cell lines which highly express Trastuzumab - A biosimilar product of Herceptin

Human epidermal growth factor receptor 2 (HER2) has been identified as a molecular target for breast cancer therapy, such as Trastuzumab (Herceptin®). This has been shown to improve patient survival substantially. The current study is aiming to locally produce an anti-HER2 monoclonal antibody (named Trastuzumab) which has an equivalent biological properties in comparison with the original version, Herceptin®). In silico design and construction of recombinant vectors, as well as the establishment of transfected cell lines with high expression of Trastuzumab were performed. Based on the protein sequences obtained from the Drugbank, the DNA sequences encoding for the light chain (Tras-Lc) and heavy chain (Tras-Hc) of Trastuzumab were optimized and integrated into pNanogen-Hygro and pNanogen-Puro vectors, respectively. The Neon Transfection System was used to co-transfect the pNanogen-Tras-Lc-Hygro and pNanogen-Tras-Hc-Puro constructs into CHO cells. Different co-transfected single-cell-colonies selected on media supplemented with hygromycin and puromycin were used for ELISA and SDS-PAGE assays to identify the CHO cell lines which highly express Trastuzumab. Based on the present results, 30μg of both constructs were suitable for DNA co-transfection. After 07 days of culture, the highest amount of Trastuzumab (561 µg/ml) was obtained from the H06LD68 cell line.

Silencing the expression of lncRNA SNHG15 may be a novel therapeutic approach in human breast cancer through regulating miR-345-5p.

Long noncoding RNA (lncRNA) short nucleolar RNA host gene 15 (SNHG15) has been found to have an oncogenic function in numerous malignancies. Nevertheless, the biological function and regulatory mechanisms of SNHG15 in breast cancer have not been fully elucidated. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression of SNHG15 and in MDA-MB-231 breast cancer cells. The expression of SNHG15 was silenced using small interfering RNA (siRNA) technology. The proliferation and migration of the cells were examined by colony formation assays, cell counting kit 8 (CCK-8) assays, and transwell assays. For the zebrafish xenograft injection experiments, cultured cells labelled with the fluorescent dye CM-DiI were injected into the perivitelline space of the larvae. This present study revealed that the expression of lncRNA SNHG15 (lnc-SNHG15) was significantly upregulated in breast cancer cells, and its overexpression was associated with the tumor. The relative expression of lnc-SNHG15 could be downregulated using siRNAs, and silencing lnc-SNHG15 inhibited the proliferation and the migration of MDA-MB-231 cells. In vivo experiments using the zebrafish xenograft model showed similar results. Mechanistically, the knockdown effect of lnc-SNHG15 could be restored by inhibiting the expression of the miR-345-5p, confirming the negative regulation between lnc-SNHG15 and miR-345-5p. Interestingly, cisplatin treatment combined with SNHG15 knockdown effectively inhibited MDA-MB-231 cell proliferation and migration in the zebrafish xenograft compared to negative controls. In conclusion, lnc-SNHG15 knockdown increased miR-345-5p expression and negated cisplatin resistance in breast cancer cells, and thus, lnc-SNHG15 may be a potential novel target for breast cancer therapy.

USP14 regulates cell cycle progression through deubiquitinating CDK1 in breast cancer.

Abnormal proliferation and cell cycle perturbation are the main hallmarks of breast cancer. Cyclin-dependent kinase 1 (CDK1) is one of the key kinases for cell transition from the G2 phase to M phase during the cell cycle progression. However, little is known about the degradation mechanisms of CDK1. USP14 (ubiquitin-specific processing protease 14) is an important proteasome-associated deubiquitinase that is critical for proteome homeostasis and plays a crucial role in the initiation and development of cancer. In this study, we find that USP14 shows high expression in breast cancer cells and results in the abnormal proliferation of cancer cells. Furthermore, we examine cell cycle distribution by flow cytometry and find that inhibition of USP14 causes cell cycle arrest in G2/M phase. As CDK1 is the key kinase in G2/M phase, we detect the interaction between USP14 and CDK1 and the effect of USP14 on the deubiquitination of CDK1. The results reveal that USP14 interacts with CDK1 and stabilizes CDK1 by deubiquitinating K48-linked ubiquitination. In conclusion, our findings reveal an indispensable role of USP14 in regulating cell cycle progression by stabilizing CDK1 in breast cancer, suggesting that USP14 may be used as a potential therapeutic target in breast cancer therapy.

Hybrid Lipid Nanoparticles Loaded with Doxorubicin for the Therapy of Breast Cancer

Breast cancer is the leading cause of death in women and its incidence is growing fast worldwide. Due to the poor benefits of doxorubicin (Dox), the first line chemotherapeutic drug for breast cancer treatment, the development of new drug delivery systems (DDSs) for Dox is critical to improve the breast cancer treatment efficacy. Here in this study, we used a film dispersion method to construct hybrid lipid nanoparticles (HLN) containing different lipids, including biotin conjugated lipid, during which Dox was loaded into the carrier to finally construct Dox loaded HLN (HLN/Dox) as a potential DDS for targeted breast cancer therapy. Our results showed that HLN/Dox were nanosized formulation with increased accumulation to MCF-7 cells due to biotin modification both in vitro and in vivo . In addition, the cellular cytotoxicity as well we in vivo antitumor assay also showed the promising cancer cell killing and tumor inhibition effects of HLN/Dox, which suggested its potential to be applied in future clinical practice.

Reduced Expression of SFRP1 is Associated with Poor Prognosis and Promotes Cell Proliferation in Breast Cancer: An Integrated Bioinformatics Approach

PurposeBreast carcinoma is the most frequent form of malignancy in women globally. Exploration of the breast cancer genome tiled the way for the validation of novel cancer biomarkers and to explore various mechanisms involved in the progression of carcinogenesis. The purpose of the research is to find an identification of potential gene linked to breast cancer (BC) progression and prognosis. MethodsThree datasets (GSE71053, GSE61724, and GSE36295) were downloaded from the Gene Expression Omnibus (GEO) database. An integrated analysis of several gene expression profile datasets was used to find differentially expressed genes (DEGs) in BC and normal breast tissue samples. Protein–protein interaction (PPI) network was used to verify hub genes associated with the pathogenesis and prognosis of BC. The functional enrichment and pathway analysis was performed by FunRich and cBioPortal. The expression pattern was assessed using COSMIC, GEPIA2, and BC-GenExMiner. ResultsThe results revealed that among the hub genes, Secreted Frizzled-related protein 1 (SFRP1) was a negative regulator of the Wnt pathway in breast cancer. Loss of SFRP1 may result in abnormal cellular proliferation, migration, and invasion, which may trigger cancer cells, leading to progression of the disease, poor prognosis, and therapy resistance. Lastly, the Kaplan–Meier plotter online database demonstrated that expression levels of the SFRP1 gene were related to lower survival. ConclusionThe findings of this research would provide some directive significance for further investigating the diagnostic and prognostic biomarker to facilitate the molecular targeting therapy of breast cancer; SFRP1 expression may be effective as a novel prognostic biomarker in early breast cancer.

Successive cytotoxicity control by evolutionary surface decorated electronic push-pull green ZnCr-LDH nanostructures: Drug delivery enlargement for targeted breast cancer chemotherapy

The reason for the increasing bioavailability and biocompatibility of the porous nanomaterials in the presence of different (bio)molecules is still unknown. The role of difference functional groups and their interactions with the potential bioavailability and biocompatibility is of great importance. To investigate the potential contribution of the electronic effects (especially on the surface of the porous nanomaterials) on their biomedical behavior, a series of surface-decorated green ZnCr-layered double hydroxide (LDH) porous nanocarriers is developed as a non-viral vector. Different conjugations investigated these porous LDHs for optimizing and minimizing the cytotoxicity for targeted breast cancer therapy. Quick low-temperature synthesized ZnCr-LDH nanocarriers method with enlarged drug delivery windows decorated with leaf extracts and benzamide-like molecules revealed a push-pull electronic synergistic effect on cytotoxicity and enhanced cell viability, biocompatibility, aggregations, and interactions with the cell membranes. The pre-defined model drug, doxorubicin (DOX), unraveled chemotherapy performance in response to MCF-7 cell lines, with ≈ 60% drug payload contributed from functional groups of leaf extracts. Moreover, electron-poor and electron-rich benzamide-like molecules attached to the ZnCr-LDH surface enhanced the relative cell viability up to 29% and 32%, respectively. The in vivo experiments on breast cancer of treated mice (H&E) revealed unaggregated cellular arrays and antibacterial activity against E. coli (gram-negative) and S. aureus (gram-positive) bacteria. Benzamide-like ZnCr-LDH nanocarriers showed a suitable zone of inhibition beyond 10 mm, compared to the standard. Cytotoxicity control achieved herein seems promising for the future ahead of nanomedicine.

Tension of plus-end tracking protein Clip170 confers directionality and aggressiveness during breast cancer migration

The microtubule (MT) plus-end binding protein Clip170 is associated closely with breast cancer invasion and migration. In this study, Clip170 tension observed by a newly designed cpstFRET tension probe was suggested to be positive related to breast cancer aggressiveness, which could be regulated by α-tubulin detyrosination-induced MT disassembly. Clip170 phosphorylation induced by Ribosomal protein S6 kinase (RSK) could also increase its tension and promote the conversion of a discrete comet-like Clip-170 distribution into a spotty pattern during cancer metastasis. Heightened Clip170 tension was correlated with the formation of cortactin-associated filopodia and lamellipodia, and then promoted invasion and metastasis both in vitro and in vivo. Meanwhile, Clip170 tension enhanced at the leading edge in directional migration, accompanying with IQGAP1 subcellular distribution variation. Our work indicates that the malignancy and directionality during breast cancer migration depend on the magnitude and polarization of Clip170 tension, and we suggest Clip170 tension as a new potential drug target for breast cancer therapy.

Aberrant phosphorylation inactivates Numb in breast cancer causing expansion of the stem cell pool.

Asymmetric cell division is a key tumor suppressor mechanism that prevents the uncontrolled expansion of the stem cell (SC) compartment by generating daughter cells with alternative fates: one retains SC identity and enters quiescence and the other becomes a rapidly proliferating and differentiating progenitor. A critical player in this process is Numb, which partitions asymmetrically at SC mitosis and inflicts different proliferative and differentiative fates in the two daughters. Here, we show that asymmetric Numb partitioning per se is insufficient for the proper control of mammary SC dynamics, with differential phosphorylation and functional inactivation of Numb in the two progeny also required. The asymmetric phosphorylation/inactivation of Numb in the progenitor is mediated by the atypical PKCζ isoform. This mechanism is subverted in breast cancer via aberrant activation of PKCs that phosphorylate Numb in both progenies, leading to symmetric division and expansion of the cancer SC compartment, associated with aggressive disease. Thus, Numb phosphorylation represents a target for breast cancer therapy.