Treatment Of Breast Cancer Research Articles

SANAS-Net: spatial attention neural architecture search for breast cancer detection

<p>The utilization of mammography images plays a vital role in the prompt detection and treatment of breast cancer. Breast imaging techniques aid medical professionals in assessing the dimensions, morphology, and spatial orientation of breast lesions, facilitating the differentiation between benign and malignant conditions. Breast tissue can vary widely in terms of density, composition, and structure, leading to complexities in distinguishing between benign and malignant conditions. The primary contribution of this paper is the proposal of a spatial attention-based neural architecture search network (SANAS-Net) technique that incorporates a spatial attention mechanism, enabling the model to learn and prioritize key regions within mammograms (MMs). Multi-head attention is employed within the transformer blocks to effectively capture a wide range of spatial relations and feature interactions. Global contextual information was integrated into the transformer blocks by means of introducing positional embeddings. Several practical studies have been undertaken to verify the effectiveness of our methodology in identifying fully attentive networks that exhibit good performance in distinguishing between malignant and benign breast cancer cases. The experimental study reached a test accuracy of 89.95%, which is way higher than previously proposed algorithms for mammography imagebased breast cancer detection.</p>

Functions and mechanisms of RNA m6A regulators in breast cancer (Review).

Breast cancer (BC) is a major malignant tumor in females and the incidence rate of BC has increased worldwide in recent years. N6‑methyladenosine (m6A) is a methylation modification that occurs extensively in eukaryotic RNA. The abnormal expression of m6A and related regulatory proteins can activate or inhibit certain signal pathways or oncogenes, thus affecting the proliferation, metastasis and prognosis of BC. Numerous studies have shown that m6A regulator disorder exists in BC, and this disorder can be reversed. Therefore, m6A is predicted as a potential therapeutic target for BC. However, the molecular mechanism of m6A RNA methylation regulating the occurrence and development of BC has not been comprehensively elucidated. In this review article, the functions of various m6A regulators and the specific mechanisms of certain regulators of the progress of BC were summarized. Furthermore, the dual role of RNA methylation in tumor progression was discussed, concluding that RNA methylation can not only lead to tumorigenesis but at times give rise to inhibition of tumor formation. In addition, further comprehensive analysis on mechanisms of m6A regulators in BC is conducive to screening effective potential targets and formulating targeted treatment strategies, which will provide new methods for the prevention and treatment of BC.

Coping with modesty during radiotherapy for breast cancer: a multicentric study.

Breast cancer is the most frequently diagnosed tumour, representing nearly 30% of all new cases in women. Radiotherapy (RT) plays a crucial role in the management of breast cancer. The objective of this study is to assess modesty in patients undergoing RT for breast cancer and take their suggestions and ideas into consideration to enhance the quality of treatment in this regard. The study enrolled 555 breast cancer patients undergoing adjuvant RT in three Italian centres. Patients completed a self-test questionnaire assessing their comfort level concerning modesty during therapy and their relationship with strangers and healthcare professionals. The impact of religious views and potential changes in sexuality were also examined. Results showed that modesty was a common concern across the overall cohort of patients, with discomfort in being undressed during RT correlating with discomfort experienced in other daily life situations. Most patients felt more at ease with same sex healthcare workers. Age was also a major factor with younger patients generally feeling more comfortable with healthcare workers of the same age group. Interestingly, the surgical technique used (mastectomy vs. quadrantectomy) did not significantly influence modesty perceptions. Patients provided valuable suggestions to improve privacy and modesty during RT. This study demonstrates that modesty is an important issue for women undergoing RT, which can be influenced by personal characteristics and hospital-related factors. A reflection about the need to address modesty concerns and to incorporate dedicated interventions for protecting patients' physical and emotional well-being is warranted. Initiatives to improve communication, involvement, and body image support should also be integrated into the care path of patients to better their overall therapeutic experience. This study paves the way for broader research and interventions in daily cancer care.

Therapeutic Potential and Pharmacological Activities of Moscatilin in Medicine for the Treatment of Cancers and other Human Complication: A Review of the Active Components of Dendrobium Species

Background: Plant-derived byproducts have been used to treat numerous kinds of human complications in medicine since a very early age. Moscatilin is a bibenzyl compound found to be present in Dendrobium. Moscatilin, also called 4,4′-dihydroxyl-3,3′,5-trimethoxybibenzyl has potential benefits in medicine for the treatment of ovarian, lung, breast, esophageal, hepatic, colorectal, pancreatic and neck squamous cancer. Methods: The present work summarized the health-beneficial aspects of moscatilin for its effectiveness against numerous kinds of cancerous disorders in medicine. Pharmacological activities and analytical aspects of moscatilin have been analyzed in the present work through available scientific data on Google, Scopus, Science Direct, and PubMed. Results: Scientific data analysis of moscatilin signified their therapeutic effectiveness against ovarian cancer, lung cancer, breast cancer, esophageal cancer, hepatic cancer, colorectal cancer, pancreatic cancer, neck squamous cell cancer, apoptosis, and angiogenesis. Further, moscatilin has a significant effect on inflammation, Alzheimer's disease, diabetic neuropathy, and retinal ischemia. However, analytical data on moscatilin were also discussed in the present work in order to know the effective separation, isolation and identification of moscatilin. Conclusion: Scientific information on moscatilin presented in this work will be helpful to all scientific people to understand the biological importance and therapeutic potential of moscatilin in medicine.

Comparative morphology of tumour microenvironment in claudin-low and claudin-high breast cancers

BackgroundClaudin low breast cancers (BCs) exhibit more aggressive behaviour compared to claudin high types. Claudin low BCs are often characterized by features such as a higher grade, enrichment of stemness characteristics, and a propensity for metastasis. Tumour microenvironment (TME) defined as the intricate network of surrounding cells, blood vessels, and extracellular matrix components influences the behaviour of cancer cells within the breast tissue. Understanding the TME is crucial for comprehending the aggressive characteristics of claudin-low BCs. MethodsIn this study, we have studied the morphology of immune and non-immune TME using Haematoxylin and eosin (H&E)-stained slides of 15 claudin-low and 12 claudin high tissue samples of BC. ResultsTME of claudin-low BCs was observed to have a significantly higher frequency of retraction clefts (66.6%; n=10/15), immature desmoplastic response (40%; n=6/15), higher stromal cellularity (60%; n=9/15); and fibroblastic proliferation (53.3%; n=8/15) with a low prevalence of elastosis (66.6%; n=10/15). The immune microenvironment revealed a higher frequency of total (80%; n=12/15) as well as stromal (86.67%; n=13/15) and intra-tumoural TILs (60%; n=9/15) in them. ConclusionThe above morphology-based study revealed that claudin-low tumours have unique immune and non-immune TME as compared to claudin-high tumours. Future studies exploring the molecular correlates of each of the above morphological features can help in identifying novel therapeutic targets for the treatment of claudin-low BCs.

Advancements in Biotechnology and Stem Cell Therapies for Breast Cancer Patients.

This comprehensive review article examines the integration of biotechnology and stem cell therapy in breast cancer diagnosis and treatment. It discusses the use of biotechnological tools such as liquid biopsies, genomic profiling, and imaging technologies for accurate diagnosis and monitoring of treatment response. Stem cell-based approaches, their role in modeling breast cancer progression, and their potential for breast reconstruction post-mastectomy are explored. The review highlights the importance of personalized treatment strategies that combine biotechnological tools and stem cell therapies. Ethical considerations, challenges in clinical translation, and regulatory frameworks are also addressed. The article concludes by emphasizing the potential of integrating biotechnology and stem cell therapy to improve breast cancer outcomes, highlighting the need for continued research and collaboration in this field.

A Review on Nanosponges: An Idiosyncratic Approach for Delivery of Proactive Molecules

Background: A lot of work has been done by many researchers to develop a system that is targeted at a specific site. Nanosponges are one of the systems that serve this purpose and have several advantages over other methods. Objective: The article’s strategy is to provide access to data regarding the nanosponges system, including its preparation, evaluation, and advantages in various fields, such as the transportation of proteins, vaccines, biocatalysts, and drugs with enhanced bioavailability. Nanosponges also contribute significantly to the treatment of breast cancer, lung cancer, fungal infection, water treatment, and topical application than other approaches. Method: Nanosponges contain a solid, porous system in which hydrophilic or lipophilic drugs are loaded at their core in the nanocavity. All the information provided in this article was collected after analysing various reports on nanosponges available on Google Scholar, PubMed, Scopus, Web of Science, and Science Direct. It is concluded that the nanosponges have excellent aqueous solubility properties. Therefore, they can be used as carriers for drugs with poor water solubility. Moreover, greater bioavailability can be achieved by using the nanosponge approach. Conclusion: Nanosponges possess various outstanding properties that form the unique system of this approach. Nanosponges provide an effective carrier system for enzymes, proteins, vaccines, and therapeutic fields. This review provides a broad overview of the development of nanosponges, their evaluation, and the uses of nanosponges based on cyclodextrin for drug delivery.

Tremendous and infrequently adenoid cystic carcinoma of the breast without any metastasis for more than 20 years: A case report.

Breast adenoid cystic carcinoma is an extremely rare tumor that is incompletely understood, accounting for less than <0.1% of all breast cancers, with an average diameter of 3 cm, and it is extremely rare to see a large, non-metastatic breast adenoid cystic carcinoma with a diameter of about 30 cm. Since this disease is extremely rare, there are few reports in the literature and limited data on clinical diagnosis and treatment. We present a case of a 71-year-old woman with a large, non-metastatic adenoid cystic carcinoma of the left breast and share our opinion on the diagnosis and treatment of this case. A 71-year-old woman with a 20-year-old left breast mass with local bleeding and rupture for 1 hour presented to our hospital for further diagnosis and treatment. A computed tomography scan showed a large soft tissue mass shadow in the left breast and malignancy was considered. Subsequently, tissue aspiration pathology was performed and the results confirmed adenoid cystic carcinoma of the breast. Intraoperative pathology results of radical mastectomy for left breast cancer diagnosed adenoid cystic carcinoma of the breast and immunohistochemistry results of triple-negative breast cancer. Treatment of adenoid cystic carcinoma of the breast included neoadjuvant chemotherapy for breast cancer, radical mastectomy of the left breast, and postoperative chemotherapy. Initially, neoadjuvant chemotherapy for breast cancer was performed, and the TAC regimen was used to successfully reduce the size of the tumor and gain access to surgical treatment for breast cancer. The patient has recovered well after the surgery, with no wound infection or ulceration, and is now waiting for the patient's physical function to recover for postoperative chemotherapy, with no obvious discomfort. Adenoid cystic carcinoma tumors are usually around 3 cm; such a huge 30 cm adenoid cystic carcinoma of the breast is extremely rare, and it is extremely rare to find a breast malignancy that has not developed regional lymph node and distant metastases for more than 20 years. Clinicians must remain vigilant for early breast malignancies at a high age of incidence and conduct further research for diagnosis to avoid delays.

Efficacy of FERscore in predicting sensitivity to ferroptosis inducers in breast cancer.

Recent studies have highlighted the potential of ferroptosis in treating breast cancer. However, the efficacy of ferroptosis induction in the most common subtype, estrogen receptor-positive (ER + ) breast cancer, remains inadequately explored. This study unveils that both short-term and long-term treatment with ER-targeted endocrine agents sensitizes ER+ breast cancer cells to ferroptosis inducers, particularly the GPX4 inhibitor, revealing a non-mutational sensitization mechanism. Based on this finding, we introduce a 55-gene signature score (FERscore) tailored to assess ferroptosis susceptibility in breast cancer. Data from cell lines and primary tumors demonstrate significant lower FERscores in ER+ breast cancer compared to other subtypes; however, FERscores dramatically increase in endocrine-resistant ER+ tumor cells and residual tumors post-endocrine therapy. Furthermore, FERscore correlates positively with mesenchymal traits, stemness, immune cell infiltration, and cancer-associated fibroblasts enrichment, while inversely correlating with estrogen responsiveness and DNA repair capacity. Additionally, the FERscore proves effective in predicting therapeutic responses to anti-ER, anti-HER2, poly (ADP-ribose) polymerase inhibitor, and anti-angiogenesis therapies in breast cancer. In summary, ferroptosis induction emerges as a promising avenue in breast cancer therapy. The FERscore offers an innovative tool for identifying patients who may benefit from ferroptosis-inducing therapies, especially those responsive to GPX4 inhibitors.

Nodal Response and Survival After Neoadjuvant Endocrine Therapy in Hormone Receptor-Positive Breast Cancer: 20-Year Experience from a Single Institution.

Axillary response to neoadjuvant endocrine therapy (NET) for the treatment of hormone receptor-positive breast cancer (HR+ BC) is not well-described. This study was designed to characterize nodal response after NET. Patients receiving NET followed by curative intent surgery at a comprehensive cancer center from 1998 to 2022 in a prospectively collected registry were included. Patients with distant metastasis were excluded. Primary outcome was nodal pathologic complete response (pCR). Downstaging was defined as post-NET decrease in category. We included 123 patients; the majority were cT2 (n = 59) or cT3 (n = 35), and cN0 (n = 81). Median age was 70.0 years (interquartile range 62.1-76.0). Forty-two patients (34.1%) were clinically node-positive. After NET, 73 (59.8%) underwent breast-conserving surgery. All patients underwent sentinel lymph node biopsy, and 12 (9.8%) underwent completion axillary lymph node dissection. In-breast downstaging was achieved in 51 (41.5%) patients, 1 (0.8%) had breast pCR, and 14 (11.4%) had breast upstaging. Axillary downstaging was achieved in 10 (23.8%), 6 patients (14.3%) had nodal pCR, and 14 (33.3%) had axillary upstaging. At 10-year follow-up, local recurrence was 1% and distant recurrence was 14%, while disease-free survival was 82%. After adjusting for demographic and clinical factors, age was the only characteristic associated with mortality (hazard ratio 1.07, 95% confidence interval 1.01-1.13). In HR+ BC treated with NET, long-term disease-free survival is good, although nodal pCR is uncommon for cN+ patients. Future studies are needed to elucidate optimal neoadjuvant systemic therapy and to delineate oncologically safe strategies to deescalate axillary management for residual microscopic disease.

AI-based big data analysis of user-generated content to understand adherence in oral hormone receptor-positive advanced breast cancer treatment: A literature review and patient-centered approach using natural language processing

AI-based big data analysis of user-generated content to understand adherence in oral hormone receptor-positive advanced breast cancer treatment: A literature review and patient-centered approach using natural language processing

Psychological Impact of Breast Cancer Diagnosis and Treatment

Psychological Impact of Breast Cancer Diagnosis and Treatment

Somatic mutational landscape across Indian breast cancer cases by whole exome sequencing.

Breast cancer (BC) has emerged as the most common malignancy among females. The genomic profile of BC is diverse in nature and complex due to heterogeneity among various geographically different ethnic groups. The primary objective of this study was to carry out a comprehensive mutational analysis of Indian BC cases by performing whole exome sequencing. The cohort included patients with a median age of 48years. TTN, TP53, MUC16, SYNE1, and OBSCN were the frequently altered genes found in our cohort. The PIK3CA and KLC3 genes are driver genes implicated in various cellular functions and cargo transportation through microtubules, respectively. Except for CCDC168 and PIK3CA, several gene pairings were found to be significantly linked with co-occurrence. Irrespective of their hormonal receptor status, RTK/RAS was observed with frequently altered signaling pathways. Further analysis of the mutational signature revealed that SBS13, SBS6, and SBS29 were mainly observed in our cohort. This study supplements the discovery of diagnostic biomarkers and provides new therapeutic options for the improved management of BC.

Sociodemographic and clinical characteristics associated with rehabilitation services utilization in older women with early-stage breast cancer from SEER-Medicare 2009-2018.

Rehabilitation services are recommended by clinical practice guidelines following breast cancer treatment, yet little is known about how utilization may vary by patient-level characteristics which we aimed to study using SEER-Medicare data. Data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database was used to identify non-metastatic breast cancer survivors aged ≥ 66years diagnosed between 2011 and 2016. Rehabilitation services delivered 0-11months post-diagnosis were identified via outpatient or physician visit claims. Descriptive statistics and associations between patient characteristics and rehabilitation services were calculated using modified Poisson models estimating relative risk (RR) and corresponding 95% confidence intervals (CIs). Of 55,539 breast cancer survivors, 33% (n = 18,244) had received any type of rehabilitative services. Survivors were a mean age of 75years (SD 6.7), 88% White, 86% urban-dwelling, and 21% Medicare/Medicaid dually enrolled. In adjusted models, patients aged > 75 vs. ≤ 75 were 6% (RR 0.94, 95% CI 0.92-0.96) less likely to have received rehabilitative services. Survivors in an area with greater educational attainment vs. less educational attainment, White vs. non-White, or living in a rural vs. urban area were 26% (1.26, CI 1.22-1.30), 6% (1.06, CI 1.02-1.11), and 6% (1.06, CI 1.02-1.10) more likely to have received rehabilitative services, respectively. The largest differences in rehabilitation utilization were observed for survivors of differing educational and treatment statuses. Further research is needed on barriers, access, and delivery of rehabilitation services, specifically for breast cancer survivors who are older-aged, non-White, or Medicare/Medicaid dual eligible.

Morin overcomes doxorubicin resistance in human breast cancer by inducing DNA damage and modulating the LKB1/AMPK/mTORC1 signaling pathway.

Breast cancer chemoresistance hampers chemotherapy efficacy; researchers investigate the pharmacological activities of natural products for potential solutions. This study aimed to determine the effect of morin, a bioflavonoid isolated from Maclura pomifera, on two Dox-resistant human breast cancer cell lines MDA-MB-231 (MDA-DR) and MCF-7 (MCF-DR). Sulforhodamine B and colony-forming assays demonstrated the cytotoxic effect of morin on both cell lines. Morin induced DNA damage and reduced the DNA repair mechanism, a feature of chemoresistance. In addition, morin reduced the protein expressions of cell cycle regulators, such as cyclin D1, CDK4, cyclin E1, cyclin B1, and p-Rb, thereby halting cell cycle progression. Moreover, morin slightly reduced PARP and Bcl-xL expressions but left LC3-II and RIPK3 expressions unchanged. Annexin-V/7-AAD analysis showed morin increased 7-AAD positive cells and annexin-V positive cells among MDA-DR and MCF-DR cells, respectively. In addition, morin increased p-AMPK and p-LKB1 levels; and, thus, inhibited phosphorylation of the mTOR pathway, but decreased t-AMPK levels by inducing lysosomal degradation, and AICAR, an AMPK activator, reduced Raptor, cyclin D1, CDK4, cyclin E1 and phosphorylated, and total mTOR levels, indicating AMPK is a key player in inducing cell death. Also, morin modulated MAPK phosphorylation and attenuated p-Akt and p-GSK3αβ levels; and thus, inhibited cell survival. In addition, morin suppressed tumor growth in our MDA-DR xenografted mouse model. These findings indicate that morin is a potential treatment for Dox-resistant breast cancer and that it does so by inducing DNA damage and modulating the LKB1/AMPK/mTORC1 pathway, along with regulating the MAPK, and Akt/GSK3αβ signaling pathways.

Global Study on the Accuracy of Human Epidermal Growth Factor Receptor 2-Low Diagnosis in Breast Cancer.

Recently, a new type of antibody-drug conjugate, trastuzumab-deruxtecan (T-DXd), has been approved for the treatment of metastatic breast cancer with low level of human epidermal growth factor receptor 2 (HER2) gene expression. Thereby, eligibility relies on an accurate diagnosis of HER2-low status defined by immunohistochemistry IHC 1+/2+ with no gene amplification. To assess pathologists' accuracy and training efficacy in the diagnosis of HER2-low. Agreement rates of HER2-low scoring in breast cancer tissue were assessed between expert consensus and real-world pathologists (n = 77 from 14 countries) before and after a specific 4-hour training for HER2-low detection. Two assays were evaluated, the Ventana Pathway 4B5 CDx and the Dako HercepTest (polyclonal). Concordance of the pathologists with consensus score and efficacy of training were measured by Cohen κ, overall rater agreement, and receiver operating characteristic (ROC) curve statistics. In the Ventana 4B5 HER2-low category, baseline agreement rates were >80% but <90%. Negative percentage agreement was improved from 80.6% to 91.1% by training. In the HER2-0 category, positive percentage agreement (74.6%) was the only parameter below the 80% benchmark but was significantly improved to 89.2% after training. Training efficacy was confirmed by ROC curve analysis, which shows improvement for the identification of HER2-0 and HER2-low cases. Finally, in-depth examination of cases with discordant HER2 status disclosed specific issues of HER2-low underscoring and overscoring. The ability of pathologists to achieve acceptable diagnostic accuracy in identifying patients with HER2-low breast cancer could be enhanced by short-term training. Potential routes to improve the quality of HER2-low scoring in clinical practice have been identified.

Acute toxicity of hypofractionated radiotherapy for Japanese breast cancer patients after surgery: a single center prospective observational study (HyPORT-BC).

This single center prospective observational study was conducted to evaluate the acute toxicity of hypo-fractionated radiotherapy for Japanese breast cancer patients after surgery. This study recruited patients who were scheduled for moderately hypo-fractionated radiotherapy including supraclavicular lymph node area (Cohort M) or ultra-hypo-fractionated radiotherapy for the conserved breast (Cohort U) as postoperative treatment for breast cancer. Radiotherapy plans were generated using automated planning system. Irradiation of 42.5Gy/16 fractions (Cohort M) or 26Gy/5 fractions (Cohort U) was delivered, and boost irradiation of 10Gy/5 fractions was added as needed. The primary endpoint was the proportion of grade ≥ 2 acute adverse events within 90days. The toxicities were evaluated using CTCAE ver 5.0. Between January 2023 and December 2023, 123 patients (81 in Cohort M and 42 in Cohort U) were enrolled. All the included patients were Japanese and completed their planned radiotherapy and were also able to be evaluated for acute adverse events. Grade 1/2/3-5 acute adverse events were observed in 67/12/0 for Cohort M and 31/4/0 for Cohort U. The proportion of grade ≥ 2 acute adverse events within 90days was 15% (95% confidence interval 8-24%) for Cohort M and 10% (95% confidence interval 3-23%) for Cohort U. The proportion of acute toxicity of hypo-fractionated radiotherapy for Japanese breast cancer patients after surgery was shown to be acceptable in this study.

Simultaneous estimation of paclitaxel and bortezomib via LC-MS/MS: pharmaceutical and pharmacokinetic applications.

Aim & Objective: This study evaluates the potential of combining paclitaxel (PTX) and bortezomib (BTZ) for breast cancer therapy. Materials & Methods: The nanoformulation was optimized via Box-Behnken Design (BBD), with method validation adhering to US-FDA guidelines. Results: Multiple reaction monitoring transitions for PTX, BTZ and internal standard were m/z 855.80→286.60, 366.80→226.00 and 179.80→110.00, respectively. Elution done on C18 Luna column with 0.1% FA in MeOH:10mM ammonium acetate. The size of nanoformulation was 133.9±1.97nm, PDI 0.19±0.01 and zeta potential -19.20±1.36mV. Pharmacokinetics showed higher Cmax for PTX-BTZ-NE (313.75±10.71ng/ml PTX, 11.92±0.53ng/ml BTZ) versus free PTX-BTZ (104±13.06ng/ml PTX, 1.9±0.08ng/ml BTZ). Conclusion: Future findings will contribute to the treatment of breast cancer using PTX and BTZ.

Doxorubicin downregulates cell cycle regulatory hub genes in breast cancer cells.

Breast cancer (BC) is the leading commonly diagnosed cancer in the world, with complex mechanisms underlying its development. There is an urgent need to enlighten key genes as potential therapeutic targets crucial to advancing BC treatment. This study sought to investigate the influence of doxorubicin (DOX) on identified key genes consistent across numerous BC datasets obtained through bioinformatic analysis. To date, a meta-analysis of publicly available coding datasets for expression profiling by array from the Gene Expression Omnibus (GEO) has been carried out. Differentially Expressed Genes (DEGs) identified using GEO2R revealed a total of 23 common DEGs, including nine upregulated genes and 14 downregulated genes among the datasets of three platforms (GPL570, GPL6244, and GPL17586), and the commonly upregulated DEGs, showed significant enrichment in the cell cycle in KEGG analysis. The top nine genes, NUSAP1, CENPF, TPX2, PRC1, ANLN, BUB1B, AURKA, CCNB2, and CDK-1, with higher degree values and MCODE scores in the cytoscape program, were regarded as hub genes. The hub genes were activated in disease states commonly across all the subclasses of BC and correlated with the unfavorable overall survival of BC patients, as verified by the GEPIA and UALCAN databases. qRT-PCR confirmed that DOX treatment resulted in reduced expression of these genes in BC cell lines, which reinforces the evidence that DOX remains an effective drug for BC and suggests that developing modified formulations of doxorubicin to reduce toxicity and resistance, could enhance its efficacy as an effective therapeutic option for BC.

EZH2 PROTACs target EZH2- and FOXM1-associated oncogenic nodes, suppressing breast cancer cell growth.

Breast cancer (BC) remains the second leading cause of cancer-related mortalities in women. Resistance to hormone therapies such as tamoxifen, an estrogen receptor (ER) inhibitor, is a major hurdle in the treatment of BC. Enhancer of zeste homolog 2 (EZH2), the methyltransferase component of the Polycomb repressive complex 2 (PRC2), has been implicated in tamoxifen resistance. Evidence suggests that EZH2 often functions noncanonically, in a methyltransferase-independent manner, as a transcription coactivator through interacting with oncogenic transcription factors. Unlike methyltransferase inhibitors, proteolysis targeting chimeras (PROTAC) can suppress both activating and repressive functions of EZH2. Here, we find that EZH2 PROTACs, MS177 and MS8815, effectively inhibited the growth of BC cells, including those with acquired tamoxifen resistance, to a much greater degree when compared to methyltransferase inhibitors. Mechanistically, EZH2 associates with forkhead box M1 (FOXM1) and binds to the promoters of FOXM1 target genes. EZH2 PROTACs induce degradation of both EZH2 and FOXM1, leading to reduced expression of target genes involved in cell cycle progression and tamoxifen resistance. Together, this study supports that EZH2-targeted PROTACs represent a promising avenue of research for the future treatment of BC, including in the setting of tamoxifen resistance.