Strategy For Treatment Of Breast Cancer Research Articles

Preclinical multi-physiologic monitoring of immediate-early responses to diverse treatment strategies in breast cancer by optoacoustic imaging.

Optoacoustic imaging enables the measurement of tissue oxygen saturation (sO2) and blood perfusion while being utilized for detecting tumor microenvironments. Our aim was to employ multispectral optoacoustic tomography (MSOT) to assess immediate-early changes of hemoglobin level and sO2 within breast tumors during diverse treatments. Mouse breast cancer models were allocated into four groups: control, everolimus (EVE), paclitaxel (PTX), and photodynamic therapy (PDT). Hemoglobin was quantified daily, as well as sO2 and blood perfusion were verified by immunohistochemical (IHC) staining. MSOT showed a temporal window of enhanced oxygenation and improved perfusion in EVE and PTX groups, while sO2 consistently remained below baseline in PDT. The same results were obtained for the IHC. Therefore, MSOT can monitor tumor hypoxia and indirectly reflect blood perfusion in a non-invasive and non-labeled way, which has the potential to monitor breast cancer progression early and enable individualized treatment in clinical practice.

Genomic and transcriptomic analysis of breast cancer identifies novel signatures associated with response to neoadjuvant chemotherapy

BackgroundNeoadjuvant chemotherapy (NAC) has become a standard treatment strategy for breast cancer (BC). However, owing to the high heterogeneity of these tumors, it is unclear which patient population most likely benefit from NAC. Multi-omics offer an improved approach to uncovering genomic and transcriptomic changes before and after NAC in BC and to identifying molecular features associated with NAC sensitivity.MethodsWe performed whole-exome and RNA sequencing on 233 samples (including matched pre- and post-treatment tumors) from 50 BC patients with rigorously defined responses to NAC and analyzed changes in the multi-omics landscape. Molecular features associated with NAC response were identified and validated in a larger internal, and two external validation cohorts, as well as in vitro experiments.ResultsThe most frequently altered genes were TP53, TTN, and MUC16 in both pre- and post-treatment tumors. In comparison with pre-treatment tumors, there was a significant decrease in C > A transversion mutations in post-treatment tumors (P = 0.020). NAC significantly decreased the mutation rate (P = 0.006) of the DNA repair pathway and gene expression levels (FDR = 0.007) in this pathway. NAC also significantly changed the expression level of immune checkpoint genes and the abundance of tumor-infiltrating immune and stroma cells, including B cells, activated dendritic cells, γδT cells, M2 macrophages and endothelial cells. Furthermore, there was a higher rate of C > T substitutions in NAC nonresponsive tumors than responsive ones, especially when the substitution site was flanked by C and G. Importantly, there was a unique amplified region at 8p11.23 (containing ADGRA2 and ADRB3) and a deleted region at 3p13 (harboring FOXP1) in NAC nonresponsive and responsive tumors, respectively. Particularly, the CDKAL1 missense variant P409L (p.Pro409Leu, c.1226C > T) decreased BC cell sensitivity to docetaxel, and ADGRA2 or ADRB3 gene amplifications were associated with worse NAC response and poor prognosis in BC patients.ConclusionsOur study has revealed genomic and transcriptomic landscape changes following NAC in BC, and identified novel biomarkers (CDKAL1P409L, ADGRA2 and ADRB3) underlying chemotherapy resistance and poor prognosis, which could guide the development of personalized treatments for BC.

Computational insights into overcoming resistance mechanisms in targeted therapies for advanced breast cancer: focus on EGFR and HER2 co-inhibition

In the present study, the formation of a heterodimer involving both epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) has been explored as a potential therapeutic mechanism to inhibit the progression of breast cancer. Virtual screening using molecular docking resulted in the three hit compounds (ZINC08382411, ZINC08382438, and ZINC08382292) with minimum binding scores and commonly binding to both receptors. Further, MD simulation analysis of these complexes illustrated the high stability of these compounds with EGFR and HER2. RMSD showed that ZINC08382411 displayed the most stable RMSD of 2 - 3 Å when bound to both receptors, suggesting to have strong compatibility with the active site of the receptor. Hydrogen bond analysis showed that ZINC08382411 forms the maximum number of H-bonds (2 to 3) in both EGFR and HER2 bound complexes, with the highest occupancy of 62% and 79%, respectively. Binding free energy calculation showed that ZINC08382411 possesses maximum affinity towards both the receptors with ΔGbind = −129.628 and −164.063 kJ/mol, respectively. This approach recognizes the significance of EGFR and HER2 in breast cancer development and aims to disrupt their collaborative signaling, which is known to promote the antagonistic behavior of cancer cells. By focusing on this EGFR/HER2 heterodimer, the study offers a promising avenue for identifying a potential candidate (ZINC08382411) that may inhibit breast cancer cell growth and potentially improve patient outcomes. The study’s findings may contribute to the ongoing efforts to advance breast cancer treatment strategies. Communicated by Ramaswamy H. Sarma

Evaluation of Relationship between Intrinsic Radiosensitivity (Survival Fraction at 2 Gy) and Gamma-H2AX Test and Apoptosis of Lymphocytes in Breast Cancer Patients.

Radiotherapy is one of the routine treatment strategies for breast cancer (BC) patients. Different responses of the patient to radiation due to different intrinsic radiosensitivity (RS) were induced to the researcher try to introduce a standard assay for the prediction of RS. Clonogenic assay is recognized as a gold standard method in this subject but because of some of its disadvantages, it is needed for alternative assays. In this study, two assays were evaluated for this reason in ten BC patients with different RSs. The peripheral blood of 10 volunteers with BC was obtained, and the peripheral blood mononuclear cells were extracted. After exposed with 2 Gy, survival fraction at 2 Gy (SF2) was calculated by clonogenic assay. γ-H2AX assay was performed for all patients, and apoptosis assay was evaluated for three represented categorized patients. RS of patients showed SF2 and categorized in three groups (high, medium, and low RS). Double-strand breaks (DSBs) were decreased in high radiosensitive patients, but the residual DSBs were clearly higher than other two groups. It is shown that the repair system in these patients is lower active than others. Apoptosis frequency in patient 4 is highly active which could induce the enhancement of her RS. γ-H2AX and apoptosis assays could predict the intrinsic RS, but evaluation of them separately is not sufficient for this aim. It is necessary to consider all the parameters together and consideration of the combination of assays could fit a better prediction of intrinsic RS.

Circular RNAs in breast cancer diagnosis, treatment and prognosis.

Breast cancer has surpassed lung cancer to become the most common malignancy worldwide. The incidence rate and mortality rate of breast cancer continue to rise, which leads to a great burden on public health. Circular RNAs (circRNAs), a new class of noncoding RNAs (ncRNAs), have been recognized as important oncogenes or suppressors in regulating cancer initiation and progression. In breast cancer, circRNAs have significant roles in tumorigenesis, recurrence and multidrug resistance that are mediated by various mechanisms. Therefore, circRNAs may serve as promising targets of therapeutic strategies for breast cancer management. This study reviews the most recent studies about the biosynthesis and characteristics of circRNAs in diagnosis, treatment and prognosis evaluation, as well as the value of circRNAs in clinical applications as biomarkers or therapeutic targets in breast cancer. Understanding the mechanisms by which circRNAs function could help transform basic research into clinical applications and facilitate the development of novel circRNA-based therapeutic strategies for breast cancer treatment.

Pistacia lentiscus L. revealed in vitro anti-proliferative activity on MCF-7 breast cancer cells and in vivo anti-mammary cancer effect on C57BL/6 mice through necrosis, anti-inflammatory and antioxidant enhancements.

Inflammation and oxidative stress are two interconnected processes that play a role in cancer development and progression. In the present research, we aimed to evaluate the anticancer effect of Pistacia lentiscus L. (PL) essential oil (EO) in vitro against MCF-7 breast cancer cells and in vivo in DMBA-mammary cancer induction on female C57BL/6 mice model as well as to investigate its anti-inflammatory and antioxidant potential as implicated mechanism. Our results revealed a new chemotypes-profile of 39 bio-compounds of PL EO. The main chemotypes were terpenoid and ketone compounds. In vitro, PL EO had a potent anti-proliferative activity against MCF-7 cells. In vivo, PL reduced the tumor number, volume, weight and burden values as compared to the DMBA-positive control group (p<0.05). Histopathology data confirmed the protective effect of PL traduced by the presence of necrosis area. PL EO revealed improvement on inflammatory perturbation in the C-RP levels and the complete blood cell count. Finally, PL improved oxidative disorders of lipid peroxidation, thiol groups, hydrogen peroxide and antioxidant enzymes depletion in plasma and mammary tissues. Also, a potent plasma scavenging capacity has been detected. Our data suggested that PL chemotypes inhibited cell proliferation, exerting a potential protective effect against DMBA-mammary cancer through anti-inflammatory and antioxidant enhancements. Targeting inflammation and oxidative stress may represent a promising strategy for breast cancer prevention and treatment.

Intraductal photothermal ablation: a noninvasive approach for early breast cancer treatment and prevention.

Background: Innovative treatment strategies for early-stage breast cancer (BC) are urgently needed. Tumors originating from mammary ductal cells present an opportunity for targeted intervention. Methods: We explored intraductal therapy via natural nipple openings as a promising non-invasive approach for early BC. Using functional Near-infrared II (NIR-II) nanomaterials, specifically NIR-IIb quantum dots conjugated with Epep polypeptide for ductal cell targeting, we conducted in situ imaging and photothermal ablation of mammary ducts. Intraductal administration was followed by stimulation with an 808 nm laser. Results: This method achieved precise ductal destruction and heightened immunological responses in the microenvironment. The technique was validated in mouse models of triple-negative BC and a rat model of ductal carcinoma in situ, demonstrating promising therapeutic potential for localized BC treatment and prevention. Conclusion: Our study demonstrated the effectiveness of NIR-II nanoprobes in guiding non-invasive photothermal ablation of mammary ducts, offering a compelling avenue for early-stage BC therapy.

Harnessing BRCA Advances: Revolutionizing Breast Cancer Diagnosis and Treatment

Advancements in understanding BRCA gene mutations have reshaped breast cancer management, ushering in a new era of precision oncology. This review explores the transformative impact of BRCA research on breast cancer diagnosis and treatment strategies, emphasizing the pivotal role of genetic testing, targeted therapies, and personalized medicine approaches. Harnessing BRCA advances offers unprecedented opportunities for early detection, risk stratification, and tailored treatment modalities, fundamentally altering the landscape of breast cancer care. Central to harnessing BRCA advances is the widespread adoption of genetic testing for BRCA mutations, enabling the identification of individuals at heightened risk of hereditary breast cancer. Genetic testing informs risk stratification and facilitates personalized screening and preventive interventions, including risk-reducing surgeries and enhanced surveillance protocols. Moreover, genetic testing guide’s treatment decisionmaking by identifying candidates for targeted therapies, such as poly (ADP-ribose) polymerase (PARP) inhibitors, which have demonstrated efficacy in BRCA-mutated breast cancers, offering new avenues for precision medicine in oncology. The integration of targeted therapies tailored to BRCA-related breast cancer subtypes represents a paradigm shift in treatment approaches, providing novel strategies to optimize patient outcomes. PARP inhibitors have emerged as a promising therapeutic option for BRCA-mutated breast cancers, leading to improved progression-free survival and overall survival in metastatic settings. On-going research endeavours aim to elucidate molecular mechanisms of treatment response and resistance, paving the way for the development of innovative therapeutic strategies to address unmet clinical needs and further enhance the efficacy of precision oncology in breast cancer management.

The role of miR-133a in silibinin-mediated inhibition of the PI3K/AKT/mTOR pathway in MCF-7 breast carcinoma cells.

Breast cancer is particularly severe in women. Research highlights the crucial role of miRNAs in key cellular processes, showcasing their intricate interactions with the oncogenic PI3K/AKT/mTOR (PAM) signaling pathway and underscoring their significant role as tumor suppressors. The effect of silibinin on cell growth and survival was evaluated using an MTT assay. Bioinformatics analysis identified putative miR-133a targets inside the PAM pathway. After incubating MCF-7 cells with silibinin, we measured miR-133a, EGFR, PI3K, AKT, PTEN, and mTOR expression levels using qRT-PCR. Furthermore, protein expression levels of mTOR were assessed using Western blotting. The MTT experiment displayed that silibinin effectively inhibits MCF-7 cell proliferation in a time- and dose-dependent manner. Silibinin's IC50 value, determined at 370 μM after 48 hours, was established. qRT-PCR analysis at this IC50 concentration highlighted reduced expression of EGFR, PI3K, AKT, PTEN, and mTOR mRNAs, alongside increased miR-133a expression. Notably, miR-133a exhibited a negative correlation with both EGFR and PIK3C2A expression. Furthermore, western blotting confirmed silibinin's capacity to diminish p-mTOR protein levels, the ultimate element of the PAM signaling pathway. The findings enhance comprehension of silibinin's impact on PAM signaling and miR-133a expression, offering promise for targeted therapies in disrupting oncogenic pathways in MCF-7 breast cancer cells. This insight could advance breast cancer treatment strategies.

Therapeutic Vaccines in Breast Cancer

Breast cancer (BC) is a major worldwide health issue, characterised by an increasing occurrence in both males and females. The classification of breast cancer subgroups is determined by variations in hormone receptor expression. Although traditional breast cancer therapies, including chemotherapy, surgery, and radiotherapy, have demonstrated effectiveness in the treatment of patients, they are frequently associated with significant adverse effects and recurrence. The emergence of therapeutic vaccines has become a promising option for the field of immunotherapy. These vaccines enhance the body’s immune system to identify and eliminate cancerous tumour cells. The current approach to vaccine therapy for breast cancer focuses on the targeting of two main categories of antigens: tumour associated antigens and tumour specific antigens. Excitingly, multiple vaccine strategies for breast cancer treatment have been employed, all of which have demonstrated promise and effectiveness in clinical studies. Currently, proposed vaccine types include peptide-based vaccines, whole tumour cell vaccines, DNA/RNA-based vaccines, dendritic cell vaccines, and viral-vector vaccines, etc. This review examined the present state of different types of vaccines in breast cancer therapy, including the therapeutic mechanism and the treatment outcomes.

Chimeric Antigen Receptor-T Cell Therapy with Breast Cancer

Breast cancer (BC) poses an increasingly serious threat to the women's health. In 2020, there will be 2.26 million new cases of BC, surpassing lung cancer for the first time and becoming the world's "first cancer". BC is distinguished by its intense invasion, extreme malignancy, and dismal outlook. High attention is needed. Chimera Antigen Receptor-T(CAR-T) has the potential to modify T cells and direct them towards particular tumor cells. It has made unheard-of advancements in hematological cancers since it was originally authorized for use in B-cell derived malignant tumors in 2017. In recent years, it has greatly reshaped the pattern of cancer treatment. At present, accumulated evidence suggests that this therapy may become the feasible treatment strategy for the solid tumors. This review will describe the main goals of this therapy for BC, list the challenges it faces, and offer the solutions to these problems, offering a unique strategy for breast cancer treatment.

Single-cell morphological and transcriptome analysis unveil inhibitors of polyploid giant breast cancer cells in vitro

Considerable evidence suggests that breast cancer therapeutic resistance and relapse can be driven by polyploid giant cancer cells (PGCCs). The number of PGCCs increases with the stages of disease and therapeutic stress. Given the importance of PGCCs, it remains challenging to eradicate them. To discover effective anti-PGCC compounds, there is an unmet need to rapidly distinguish compounds that kill non-PGCCs, PGCCs, or both. Here, we establish a single-cell morphological analysis pipeline with a high throughput and great precision to characterize dynamics of individual cells. In this manner, we screen a library to identify promising compounds that inhibit all cancer cells or only PGCCs (e.g., regulators of HDAC, proteasome, and ferroptosis). Additionally, we perform scRNA-Seq to reveal altered cell cycle, metabolism, and ferroptosis sensitivity in breast PGCCs. The combination of single-cell morphological and molecular investigation reveals promising anti-PGCC strategies for breast cancer treatment and other malignancies.

Economic Evaluation of Neoadjuvant Treatment Strategies for HER2 Positive Breast Cancer: A Systematic Review

Context: There are several neoadjuvant treatment strategies for HER2-positive breast cancer (BC). Studies have investigated different aspects of these strategies and presented different findings. Objectives: This study aimed at collecting and interpreting economic evaluation studies related to neoadjuvant treatment strategies for HER2-positive BC. Methods: In this systematic review, PubMed, Web of Science (WOS), ScienceDirect, and Scopus databases were searched without a time limit between May and October 2023. Google Scholar search engine was also used to complete the search process. Two authors independently determined the eligibility of the study. To assess the quality of the studies, the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) guidelines were used. Disagreements were resolved by discussion or consultation with a third researcher. As this review is descriptive, numerical data were not extracted for statistical analysis. Results: Out of 234 studies found in the first stage, 21 studies from 14 countries were included. The strategies that have been approved by studies include THP (taxol, trastuzumab, pertuzumab), PTD (Pertuzumab in combination with trastuzumab and docetaxel), TH (docetaxel and trastuzumab), T-DM1 (trastuzumab emtansine), and HP (trastuzumab plus pertuzumab). Conclusions: The findings of this systematic review show that the reported strategies in the treatment of HER2-positive BC patients are cost-effective in different settings. While the findings of this review provide largely positive results, the characteristics of each strategy should be considered.

Delta-Radiomics Based on Dynamic Contrast-Enhanced MRI for Predicting Lymphovascular Invasion in Invasive Breast Cancer

Treatment strategies for invasive breast cancer require accurate lymphovascular invasion (LVI) predictions. This study aimed to investigate the effectiveness of delta radiomics based on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for assessing LVI and develop a nomogram to aid treatment decisions. Overall, 293 patients with resectable invasive breast cancer underwent preoperative DCE-MRI. Radiomic features were extracted from pre-contrast (A0), first post-contrast (A1), and subtracted images of A0 and A1. Three radiomics models were developed using several data analyses; logistic analyses were performed to identify radiological features to predict the LVI status. A hybrid model integrating both radiological features and optimal radiomics was developed. Receiver operating characteristic analysis was employed to evaluate model performance, using the area under the curve (AUC) as a quantitative metric for discriminative ability. In the test set, the Radiomics-Delta model, with 17 radiomic features, had an AUC of 0.781 and accuracy of 0.705. Radiomics-A0, with 10 features, had an AUC of 0.619 and accuracy of 0.523, while Radiomics-A1, with 8 features, had an AUC of 0.715 and accuracy of 0.591. The hybrid model exhibited better performance, with an AUC of 0.868 and accuracy of 0.875, than the radiological and Radiomics-Delta models, with an AUC of 0.759 and 0.781, respectively, and accuracy of 0.773 and 0.705, respectively. Compared to Radiomics-A0 and Radiomics-A1, Radiomics-Delta demonstrated superior performance. Moreover, the hybrid model incorporating Radiomics-Delta and radiological features exhibited excellent performance in determining the LVI status in cases of invasive breast cancer.

Nanoformulated 3′-diindolylmethane modulates apoptosis, migration, and angiogenesis in breast cancer cells

BackgroundIt is well-established that specific herbal plants contain natural active ingredients that have demonstrated anti-cancer potential. Therefore, they are considered highly beneficial as a potential adjuvant, alternative or complementary agent in anti-cancer therapy. However, the low chemical stability and limited bioavailability of 3, 3′-Diindolylmethane (DIM), a plant-derived compound used in clinical settings, limit its therapeutic applications. To overcome this challenge, researchers have focused on developing innovative approaches to improve DIM's biological activity, such as utilizing nanoformulations. Here, we investigated the potential benefits of coating DIM nanoparticles (DIM-NPs) with PEG/chitosan in the treatment of breast cancer. Our results demonstrate the molecular mechanism underlying the activity of DIM-NPs, highlighting their potential as an effective therapeutic strategy for breast cancer treatment. MethodsDIM-PLGA-PEG/chitosan NPs were synthesised and characterised using dynamic light scattering (DLS) and evaluated the impact of these NPs on two breast cancer cell models. ResultsDIM-NPs had an average diameter of 102.3 nm and a PDI of 0.182. When treated with DIM-NPs for 48 h, both MCF7 and MDA-MB-231 cells displayed cytotoxicity at a concentration of 6.25 g/mL compared to untreated cells. Furthermore, in MDA-MB-231 cells, treatment with 2.5 μg/mL of DIM-NPs resulted in a significant decrease in cell migration, propagation, and angiogenesis which was further enhanced at 10 μg/mL. In chicken embryos, treatment with 5 μg/mL of DIM-NPs on day 2 led to a significant reduction in angiogenesis. Furthermore, this treatment induced cell death through a regulatory pathway involving the upregulation of Bax and p53, as well as the downregulation of Bcl-2. These results were supported by in-silico analysis of DIM's binding affinity to key proteins involved in this pathway, namely Bax, Bcl-2, and p53. ConclusionOur findings show that DIM-NPs induces apoptosis, inhibit migration, and reduce angiogenesis in breast cancer. However, further research using a preclinical cancer model may be necessary to determine the pharmacokinetics of DIM-NPs and ensure their safety and efficacy in vivo.

Alternative splicing in breast cancer

Alternative splicing allows a gene to produce multiple proteins and is the main source of human proteome diversity. Aberrant regulation of alternative splicing produces proteins with different structures and can lead to altered protein function, inactivation, or deleterious variants, which can have severe effects on normal cellular function, leading to many diseases, including cancer. Alternative splicing abnormalities are often found in diseases, so alternative splicing is highly correlated with diseases and treatment. According to relevant statistics, breast cancer is an important factor that threatens women’s lives and health. A common sign of tumors in humans is abnormal alternative splicing. An increasing amount of evidence shows that abnormal alternative splicing plays an important role in the occurrence and development of breast cancer. At the same time, in the related treatment of breast cancer, alternative splicing can lead to the failure of existing treatment methods and induce drug resistance. Currently, targeted therapy is still the key strategy for breast cancer treatment. In this review, we discuss the five classifications of alternative splicing and aberrant alternative splicing in breast cancer. The role of alternative splicing in the drug resistance of breast cancer is also discussed. Evidence has shown that aberrant alternative splicing can lead to drug resistance to current therapies. Because splicing factors are involved in many aspects of cancer, splicing factors may provide a new strategy for cancer treatment and a powerful tool for progress in the fight against breast cancer. Antisense oligonucleotides form a double-stranded structure by complementary pairing with mRNA, which prevents the binding of mRNA and ribosomes, thus inhibiting protein synthesis. Therefore, after finding effective targets, antisense oligonucleotides can be applied in gene therapy, drug research and development, biological research, and other fields to improve therapeutic effects.

Dual‐Energy CT in Breast Cancer: Current Applications and Future Outlooks

AbstractBreast cancer is the most prevalent cancerous tumor in women, characterized by different subtypes and varying responses to treatment. The continued evolution of breast cancer diagnosis and management has resulted in a transition from a one‐size‐fits‐all approach to a new era of personalized treatment plans. Therefore, it is essential to accurately identify the biological characteristics of breast tissue in order to minimize unnecessary biopsies of benign lesions and improve the overall clinical process, leading to reduced expenses and complications associated with invasive biopsy procedures. Challenges for future research include finding ways to predict the response of breast cancer patients to adjuvant systemic treatment.Dual‐energy CT (DECT) is a new imaging technology integrating functional imaging and molecular imaging. Over the past decade, DECT has gained relevancy, especially in oncological radiology. This article proposed a literature review of the application and research status of DECT in breast cancer treatment strategy determination and prognosis prediction.

Mechanism of CDK4/6 Inhibitor Resistance in Hormone Receptor-positive Breast Cancer and Alternative Treatment Strategies.

Breast cancer (BC) is a common malignancy in women, with hormone receptor (HR)-positive subtype responsible for approximately 70% of cases. Currently, patients with metastatic HR-positive BC rely on endocrine therapy and cyclin-dependent kinase (CDK)-4/6 inhibitors for treatment. Currently, approved CDK4/6 inhibitors include palbociclib, ribociclib, and abemaciclib. However, clinical evidence of CDK-4/6 inhibitor resistance is emerging, suggesting that the gap in the knowledge of its resistance mechanism requires further investigation. This review discusses the mechanisms of CDK4/6 inhibitor resistance in BC, including both intrinsic and extrinsic mechanisms. We also discuss possible alternative strategies to overcome CDK4/6 inhibitor resistance in future clinical applications.

Liquid biopsy biomarkers to guide immunotherapy in breast cancer.

Immune checkpoint inhibitors (ICIs) therapy has emerged as a promising treatment strategy for breast cancer (BC). However, current reliance on immunohistochemical (IHC) detection of PD-L1 expression alone has limited predictive capability, resulting in suboptimal efficacy of ICIs for some BC patients. Hence, developing novel predictive biomarkers is indispensable to enhance patient selection for immunotherapy. In this context, utilizing liquid biopsy (LB) can provide supplementary or alternative value to PD-L1 IHC testing for identifying patients most likely to benefit from immunotherapy and exhibit favorable responses. This review discusses the predictive and prognostic value of LB in breast cancer immunotherapy, as well as its limitations and future directions. We aim to promote the individualization and precision of immunotherapy in BC by elucidating the role of LB in clinical practice.

Glutathione-responsive PROTAC for targeted degradation of ERα in breast cancer cells

ERα (estrogen receptor-α)-targeting PROTACs (PROteolysis TArgeting Chimeras) have emerged as a novel and promising modality for breast cancer therapeutics. However, ERα PROTACs-induced degradation in normal tissues raises concerns about potential off-tissue toxicity. Tumor microenvironment-responsive strategy provides potential for specific control of the PROTAC’s on-target degradation activity. The glutathione (GSH) level has been reported to be significantly increased in tumor cells. Here, we designed a GSH-responsive ERα PROTAC, which is generated by conjugating an o-nitrobenzenesulfonyl group to the hydroxyl group of VHL-based ERα PROTAC through a nucleophilic substitution reaction. The o-nitrobenzenesulfonyl group as a protecting group blocks the bioactivity of ERα PROTAC (ER-P1), and that can be specifically recognized and removed by highly abundant GSH in cancer cells. Consequently, the GSH-responsive ERα PROTAC (GSH-ER-P1) exhibits significantly enhanced degradation of ERα in cancer cells compared to that in normal cells, leading to a remarkable inhibition of breast cancer cell proliferation and less toxic effects on normal cells. This study provides a potentially valuable strategy for breast cancer treatment using tumor microenvironment-responsive PROTACs.