PKMYT1 Promotes Epithelial-Mesenchymal Transition Process in Triple-Negative Breast Cancer by Activating Notch Signaling

ABSTRACT Background: Triple-negative breast cancer (TNBC) is a subtype of breast cancer (BC) that lacks receptors for targeted therapy. Deeper insight into the molecular mechanisms regulating TNBC metastasis is urgently needed. The epithelial-mesenchymal transition process facilitates the metastasis of neighboring epithelial tumor cells. Protein kinase, membrane-associated tyrosine/threonine 1 (PKMYT1), a member of the Wee family of protein kinases, is upregulated in BC, and its high expression predicts poor prognosis in BC patients. Notch signaling activation is a pathognomonic feature of TNBC. PKMYT1 has been found to induce EMT in non-small cell lung cancer by activating Notch signaling. However, whether PKMYT1 exerts effects on TNBC progression by regulating Notch signaling remains unknown. Objectives: The objective of this study was to investigate whether PKMYT1 exerts effects on TNBC progression by regulating Notch signaling. Methods: Fifty cases of surgically resected BC samples (tumor and adjacent non-tumor tissue samples) were collected from patients diagnosed with BC. We measured the expression of PKMYT1 in clinical samples with real-time quantitative polymerase chain reaction (RT-qPCR). For in vitro analysis, RT-qPCR and Western blotting were conducted to evaluate PKMYT1 expression in TNBC cells. Then, the viability, migration, and invasion of TNBC cells were detected by cell counting kit-8 assays, wound healing assays, and Transwell assays. The EMT event was examined by evaluating the levels of EMT-associated proteins. For in vivo analysis, xenograft models in nude mice were established to explore PKMYT1 roles. E-cadherin and Ki67 expression in xenograft models were estimated by immunohistochemistry staining. Hematoxylin and eosin staining was performed to assess tumor metastasis. The underlying mechanisms by which PKMYT1 affected the malignant phenotypes of TNBC cells were explored by Western blotting measuring the pathway-associated proteins. Results: PKMYT1 was upregulated in BC tissues and cells, and its knockdown prevented cell proliferation, migration, invasion, and EMT event in TNBC. Mechanistically, Notch signaling was inactivated by PKMYT1 depletion, and Notch activation abolished the PKMYT1 silencing-induced inhibition in the malignant phenotypes of TNBC cells. For in vivo analysis, PKMYT1 knockdown inhibited tumorigenesis and metastasis of TNBC. Conclusion: PKMYT1 promotes EMT, proliferation, migration, and invasion of TNBC cells and facilitates tumor growth and metastasis by activating Notch signaling.

A molecular approach to triple-negative breast cancer: targeting the Notch signaling pathway

ABSTRACT Introduction Triple-negative breast cancer is an aggressive subtype of breast cancer characterized by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression. This phenotype renders triple-negative breast cancer cells refractory to conventional therapies, resulting in poor clinical outcomes and an urgent need for novel therapeutic approaches. Recent studies have implicated dysregulation of the Notch receptor signaling pathway in the development and progression of triple-negative breast cancer. Objective This study aimed to conduct a comprehensive literature review to identify potential therapeutic targets of the Notch pathway. Our analysis focused on the upstream and downstream components of this pathway to identify potential therapeutic targets. Results Modulating the Notch signaling pathway may represent a promising therapeutic strategy to treat triple-negative breast cancer. Several potential therapeutic targets within this pathway are in the early stages of development, including upstream (such as Notch ligands) and downstream (including specific molecules involved in triple-negative breast cancer growth). These targets represent potential avenues for therapeutic intervention in triple-negative breast cancer. Comments Additional research specifically addressing issues related to toxicity and improving drug delivery methods is critical for the successful translation of these potential therapeutic targets into effective treatments for patients with triple-negative breast cancer.

Down-regulation of METTL5 inhibits proliferation, migration and invasion of triple-negative breast cancer cells through Wnt/6-catenin signaling pathway / 中国药理学通报

Aim To investigate the role and potential mechanism of methyltransferase-like 5 (METTL5) in triple-negative breast cancer (TNBC) . Methods The expression of METTL5 in TNBC tumor tissues and cell lines was detected by immunohistochemistry and Western blot. After shRNA targeting METTL5 (shRNAMETTL5) was transfected into TNBC cells, cell proliferation, migration and invasion were detected by CCK-8, colony formation, wound healing and Transwell assays, respectively. Western blot was used to detect the expression of Wnt/p-catenin signaling-related key proteins. A xenograft tumor model was constructed to verify the effect of METTL5 knockdown on the growth of TNBC cells and Wnt/p-catenin signaling activity in vivo. Results The expression of METTL5 was up-regulated in TNBC tumor tissues and cell lines (P < 0. 01) . Knockdown of METTL5 significantly inhibited the proliferation, migration and invasion of TNBC cells and reduced the expression of Wnt/p-catenin signaling molecules (3-catenin, cyclin Dl, matrix metalloproteinase (MMP) -2 and MMP-7 (all P < 0. 01) . Knockdown of METTL5 reduced tumor growth and Wnt/pcatenin signaling activity in vivo. Conclusions Knockdown of METTL5 can inhibit the proliferation, migration and invasion of TNBC cells, which may be related to the inhibition of Wnt/p-catenin signaling pathway.

Modelos murinos para el estudio de cáncer de mama triple negativo / Murine models for the study of triple negative breast cancer

RESUMEN El estudio de diferentes variables, como patogénesis, perfil inflamatorio, identificación de blancos terapéuticos, eficacia de tratamientos en modelos murinos ha resultado uno de los más prácticos para el estudio preclínico del cáncer de mama triple negativo (CMTN), el subtipo de cáncer más agresivo, con limitada aplicación de tratamientos y baja tasa de sobrevivencia. Sin embargo, hay que reconocer que existen otros menores en los que se viene estandarizando la inducción del CMTN. En esta revisión se engloban los diferentes métodos de inducción que han permitido el desarrollo de CMTN y las aplicaciones terapéuticas más relevantes por el que se desarrollaron los modelos murinos con CMTN.

ABSTRACT The study of different variables, such as pathogenesis, inflammatory profile, identification of therapeutic targets, efficacy of treatments in murine models has proven to be one of the most practical for the preclinical study of triple negative breast cancer (TNBC), the most aggressive subtype of cancer, with limited application of treatments and low survival rate. However, it must be recognized that there are other minors in which the induction of TNBC is being standardized. This review encompasses the different induction methods that have allowed the development of TNBC and the most relevant therapeutic applications by which murine models with TNBC were developed.

Programmed cell death protein 1 is a marker for neoadjuvant chemotherapy response in triple-negative breast cancer

SUMMARY OBJECTIVE: Tumor-infiltrating lymphocytes are detectable in up to 75% of triple-negative breast cancer. The composition of these infiltrates may influence prognosis and is not known regarding regulatory or effector lymphocytes. The objectives of this study were to describe and quantify the composition of the tumor-infiltrating lymphocytes before and after chemotherapy (neoadjuvant chemotherapy) and to evaluate their association with complete pathological response and overall survival. METHODS: This was a retrospective observational study. Clinical and pathological data from 38 triple-negative breast cancer patients treated with neoadjuvant chemotherapy at the University Hospital (HUCFF/UFRJ), between November 2004 and November 2018, were analyzed. The Stromal tumor-infiltrating lymphocytes (Stromal tumor-infiltrating lymphocytes) have been identified on hematoxylin and eosin-stained sections according to the guidelines of the "International tumor-infiltrating lymphocytes Working Group." Immunohistochemistry studies were performed to identify T-cell subsets (i.e., CD3, CD4, CD8, and FOXP3) and T-cell exhaustion (i.e., programmed cell death protein 1). RESULTS: Statistically significant changes in stromal tumor-infiltrating lymphocyte categories were observed before and post-neoadjuvant chemotherapy, with 32% of intermediate cases becoming high. The correlation between pre-neoadjuvant chemotherapy stromal tumor-infiltrating lymphocytes and pathological response, pre-neoadjuvant chemotherapy and post-neoadjuvant chemotherapy, and stromal tumor-infiltrating lymphocytes and overall survival was not statistically significant. However, we noticed an increase of cells that favor the antitumor activity (i.e., CD3, CD8, and CD8/FOXP3 ratio) and decreased levels of cells inhibiting tumor activities (i.e., FOXP3 and programmed cell death protein 1) post-neoadjuvant chemotherapy. Importantly, programmed cell death protein 1 expression pre-neoadjuvant chemotherapy showed an association with pathological response. CONCLUSION: In this study, we observed that chemotherapy significantly increases stromal tumor-infiltrating lymphocytes, CD8 T cells, as well as CD8/FoxP3 ratio. Most importantly, programmed cell death protein 1 expression before neoadjuvant chemotherapy positively correlates with pathological response suggesting the use of programmed cell death protein 1 as a prognostic marker before neoadjuvant chemotherapy.

CLINICOPATHOLOGICAL STUDY IN TRIPLE NEGATIVE BREAST CANCER

Background and Objectives: - Carcinoma Breast is most common malignancy in females in USA and second among cases deaths in females (after lung cancer). There is considerable geographic , ethnic and racial variability in Breast cancer in evidence with about 5 fold variation throughout the world. Triple negative breast cancer is a heterogonous disease diagnosed by Immune Histo Chemistry (IHC).Triple Negative Breast cancer is characterized by tumor that do not express ER or PR and HER2neu . Proto typical Triple Negative Brest cancer is aggressive in nature and associate with poor prognosis. The Objectives of this study is to analyse the clinical and Pathological features of Triple Negative Breast Cancer and compare the result with similar studies in literature. Fifty Methods:- cases Triple negative Breast Cancer were included in this study. Clinical and pathological features and treatment were noted. Incidence Result:- of Triple Negative Breast Cancer was 35%. The median age of presentation was 45yrs. There were 4% males Triple negative Breast cancer cases out of female patients, most of patients were Pre (or) Perimenopausal(65%). 4% patients had family history of malignantly. Most common stage of presentation was stage III (46%). In Stage IV, Lung and bone metastasis was common. Ten Patients received Neoadjuvant chemo therapy (NACJ) and disease progressed in 4% while on Neoadjuvant chemotherapy, Even though 45 patients had surgery only 34 were eligible to received Adjuvant Radiotherapy. Total of 18% Patients had either progressive disease while on treatment (8%) (or) recurrence 10%. Eighteen percent patients died due to the disease. 33% patients on follow up. There were more Invasive Duct Cell carcinoma (IDCC) cases with medullary differentiations (or) Purse medullary Carcinomas (12%). No deaths Occur in the medullary variants TNBC. Majority of the tumor were high grade margins were negative in most of the cases. Incidence of Tri Inclusion:- ple negative breast cases was higher than western literature but comparable to Indian Studies. The age of Presentation was about 10 years younger than western data. Triple Negative Breast cancer was more common in young, pre (or) perimenopausal women. Small number of patients had family history, majority were state II (or) III. There was high number of progressive disease, recurrence and death while on the study (or) within less than 1 yr of treatment. Triple Negative Breast cancer is very aggressive disease with relatively better prognosis in the medullary variant Triple Negative Breast Cancer.

Carcinoma de mama triple negativo. Estudio anatomo-estadístico / Triple- negative breast cancer. An anatomical and statistical study

Introducción: El carcinoma de mama triple negativo se asocia a un comportamiento biológico más agresivo y de desfavorable pronóstico. Objetivo: Determinar la incidencia del subtipo molecular triple negativo en carcinomas mamarios y su relación con otras variables clínico-patológicas de valor pronóstico. Método: Se realizó un estudio descriptivo y retrospectivo, en el Hospital Universitario Docente «Celestino Hernández Robau» de Villa Clara, en el período comprendido de enero de 2017 a junio de 2019, con el fin de determinar la incidencia de los tumores triples negativos y su relación con las variables edad, talla tumoral, tipo y grado histológicos e índice de proliferación. Resultados: Se determinó la incidencia del subtipo molecular triple negativo en carcinomas mamarios y su relación con las formas histológicas moderada y poco diferenciadas. Conclusiones: El subtipo molecular triple negativo en carcinomas mamarios está asociado con frecuencia a: la edad posmenopáusica, el tipo histológico ductal, el grado histológico alto, altos índices de Ki-67 y talla tumoral mayor de 2 cm.

Introduction: triple-negative breast cancer has a more aggressive biological behaviour and is associated with an unfavourable prognosis. Objective: to determine the incidence of triple- negative breast cancer molecular subtypes and its relationship with other clinical and pathological variables of prognostic value. Methods: a descriptive and retrospective study was carried out at "Celestino Hernández Robau" University Teaching Hospital from Villa Clara between January 2017 and June 2019 in order to determine the incidence of triple- negative tumors and its relationship with the variables: age, tumor size, histological type and grade as well as proliferative index. Results: the incidence of triple- negative breast cancer molecular subtype and its relationship with moderate and poorly differentiated histological forms were determined. Conclusions: triple- negative breast cancer molecular subtype is frequently associated with postmenopausal age, ductal histological type, high histological grade, high Ki-67 indices and tumor size greater than 2 cm.

BRCA1 promoter methylation & its immunohistochemical correlation in sporadic breast cancer

Background & objectives: Studies have shown that apart from hereditary breast carcinomas, breast cancer susceptibility gene 1 (BRCA1) mutations conferring to its loss are seen in sporadic breast carcinomas (SBC) as well. The aim of the present study was to assess BRCA1 methylation in females presenting at King George’s Medical University, Lucknow, with SBC by both immunohistochemistry (IHC) and methylation PCR with respect to hormonal profile and various morphological prognostic parameters. The primary objective was to look for the association between BRCA1 protein expression and DNA promoter methylation. Methods: 81 mastectomy specimens from SBC of invasive breast carcinoma (no special type) were included in this study. After a detailed morphological assessment, formalin fixed paraffin embedded tissue from a representative tumour area was selected for BRCA1 IHC by heat-mediated antigen retrieval under high pH and DNA extraction and further bisulphate treatment. BRCA1 was studied for methylation by methylated and unmethylated PCR-specific primers. Results: BRCA1 promoter methylation was present in 42/81 (51.9%) participants, with significant BRCA1 protein loss (72.7%; P=0.002). A significant association between BRCA1 loss and hormonal profile was found (P=0.001); maximum in triple negative breast carcinoma (TNBC) (72%; 18/25). Most of the TNBC also harboured methylation (68%). Although not significant grade II and III tumours, lymph vascular invasion, ductal carcinoma in situ, and nodal metastasis (?3) were seen in a higher percentage in methylated tumours. Mortality in SBC was significantly associated with BRCA1 loss (30.3%; P=0.024). Interpretation & conclusions: Study results highlight the concept of “BRCAness” in SBC as well. Hence, we can confer that identification of BRCA1 loss in SBC can make it a perfect candidate for poly ADP- ribose polymerase inhibitors or cisplatin-based therapy like hereditary ones.

Salivary gland tumor: atypical presentation of breast cancer

Breast cancer is a heterogeneous disease with various histological and molecular subtypes. Among them, salivary gland tumors are rare and can be divided into three groups: pure myoepithelial differentiation, pure epithelial differentiation and myoepithelial with mixed epithelial differentiation. In the last group, adenoid cystic carcinoma stands out, a rare entity with low malignant potential. It represents less than 0.1­3% of breast cancer cases and has the most frequent clinical presentation as a palpable mass. The diagnosis is confirmed by histology and immunohistochemistry. Classically, they are low-aggressive triple-negative tumors, with overall survival and specific cancer survival at five and ten years greater than 95%. However, there are rare reports of aggressive variants with a risk of distant metastasis and death. Treatment is based on surgical resection with margins. Lymphatic dissemination is rare, and there is no consensus regarding the indication of an axillary approach. Adjuvant radiotherapy is indicated in cases of conservative surgery and should be discussed in other cases. The benefit of chemotherapy remains uncertain, as most tumors are indolent. We report a case that required individualized decisions based on its peculiarities of presentation, diagnosed in an asymptomatic elderly patient during screening, in which mammography showed heterogeneous gross calcifications clustered covering 1.6 cm. Stereotacticguided vacuum-assisted biopsy was performed, and the area was marked with a clip. The anatomopathological examination led to a diagnosis of salivary gland-type carcinoma, triple-negative. The patient underwent segmental resection of the right breast and sentinel lymph node biopsy. The final anatomopathological result was similar to that of the biopsy, with an immunohistochemicalprofile of the adenoid cystic type and two sentinel lymph nodes free of neoplasia. Considering age and histological subtype, adjuvant therapy was not indicated. Follow-up for three years showed no evidence of disease

Inhibition of CD36 and Nogo-B expression inhibited the proliferation and migration of triple negative breast cancer cells / 生物工程学报

Cluster of differentiation 36 (CD36) is a membrane glycoprotein receptor capable of binding and transporting fatty acid. Nogo-B regulates the metabolism of fatty acids in the liver and affects the development of liver cancer. To date, it remains unclear whether the interaction between CD36 and Nogo-B affects the proliferation and migration of breast cancer cells. In the current study, we aimed to determine whether the interference of CD36 and Nogo-B affects the proliferation and migration of triple-negative breast cancer (TNBC) cells. The results showed that inhibition of CD36 or Nogo-B alone can inhibit the proliferation and migration of TNBC cells, and the inhibitory effect was more pronounced when CD36 and Nogo-B were inhibited simultaneously. Meanwhile, it was found that inhibition of CD36 and Nogo-B expression can inhibit the expression of Vimentin, B-cell lympoma-2 (BCL2) and proliferating cell nuclear antigen (PCNA). In vivo, knockdown of CD36 or Nogo-B in E0771 cells reduced its tumorigenic ability, which was further enhanced by knockdown of CD36 and Nogo-B simultaneously. Mechanistically, inhibition of CD36 and Nogo-B expression can decrease fatty acid binding protein 4 (FABP4) and fatty acid transport protein 4 (FATP4) expression. Moreover, overexpression of CD36 and Nogo-B-induced cell proliferation was attenuated by FABP4 siRNA, indicating that inhibition of CD36 and Nogo-B expression could inhibit the absorption and transport of fatty acids, thereby inhibiting the proliferation and migration of TNBC. Furthermore, inhibition of CD36 and Nogo-B expression activated the P53-P21-Rb signaling pathway which contributed to the CD36 and Nogo-B-inhibited proliferation and migration of TNBC. Taken together, the results suggest that inhibition of CD36 and Nogo-B can reduce the proliferation and migration of TNBC, which provides new targets for the development of drugs against TNBC.

Effect of ACE2 on the prognosis of breast cancer and its potential mechanism / 中国药科大学学报

@#This study aims to investigate the effect of transmembrane protein angiotensin converting enzyme 2 (ACE2) on the prognosis of breast cancer and its potential mechanism.Public databases were used to analyze ACE2 expression and its relationship with clinicopathological features and prognosis of breast cancer patients, combined with in vitro experiments to analyze the mechanism of action and immune relevance of ACE2 in breast cancer.Results showed that the expression of ACE2 in breast cancer tissues was significantly lower than that in normal breast tissues, and that its expression was negatively correlated with age, M stage and N1mi stage of breast cancer patients (P < 0.05).Patients with Luminal type breast cancer with high ACE2 expression had poor prognosis, while in the triple-negative breast cancer (TNBC) subtype, ACE2 showed different prognostic significance.In addition, ACE2 is closely associated with the metabolic and immune microenvironment of tumor tissue.In vitro experiments have shown that ACE2 is lowly expressed in MDA-MB-231 cells and may inhibit cell progress by downregulating matrix metalloproteinase 2（MMP2）.The results suggest that the low expression of ACE2 in breast cancer is closely associated with patient prognosis as well as metabolic and immune microenvironment, and that ACE2 may inhibit TNBC cell progress through the MMP2 pathway.

Research progress on immunotherapy for triple-negative breast cancer / 中国临床药理学与治疗学

Triple-negative breast cancer (TNBC) is a subtype of breast cancer characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). It is highly aggressive, easy to relapse, and chemotherapy remains its mainstay treatment due to the lack of therapeutic targets. In recent years, many advances have been made in the development of immunotherapy for TNBC. This review summarizes the primary modalities of immunotherapy for TNBC, including immune checkpoint inhibitors, adoptive immune cell therapy, tumor vaccines and oncolytic virus. We present the latest research progress on each treatment from the perspective of clinical study and fundamental research, while introducing the potential predictive biomarkers and resistance mechanisms of immunotherapy for TNBC.

Engineering cannabidiol synergistic carbon monoxide nanocomplexes to enhance cancer therapy via excessive autophagy

Although carbon monoxide (CO)-based treatments have demonstrated the high cancer efficacy by promoting mitochondrial damage and core-region penetrating ability, the efficiency was often compromised by protective autophagy (mitophagy). Herein, cannabidiol (CBD) is integrated into biomimetic carbon monoxide nanocomplexes (HMPOC@M) to address this issue by inducing excessive autophagy. The biomimetic membrane not only prevents premature drugs leakage, but also prolongs blood circulation for tumor enrichment. After entering the acidic tumor microenvironment, carbon monoxide (CO) donors are stimulated by hydrogen oxide (H2O2) to disintegrate into CO and Mn2+. The comprehensive effect of CO/Mn2+ and CBD can induce ROS-mediated cell apoptosis. In addition, HMPOC@M-mediated excessive autophagy can promote cancer cell death by increasing autophagic flux via class III PI3K/BECN1 complex activation and blocking autolysosome degradation via LAMP1 downregulation. Furthermore, in vivo experiments showed that HMPOC@M+ laser strongly inhibited tumor growth and attenuated liver and lung metastases by downregulating VEGF and MMP9 proteins. This strategy may highlight the pro-death role of excessive autophagy in TNBC treatment, providing a novel yet versatile avenue to enhance the efficacy of CO treatments. Importantly, this work also indicated the applicability of CBD for triple-negative breast cancer (TNBC) therapy through excessive autophagy.

Macrophage-camouflaged epigenetic nanoinducers enhance chemoimmunotherapy in triple negative breast cancer

Chemoimmunotherapy has been approved as standard treatment for triple-negative breast cancer (TNBC), but the clinical outcomes remain unsatisfied. Abnormal epigenetic regulation is associated with acquired drug resistance and T cell exhaustion, which is a critical factor for the poor response to chemoimmunotherapy in TNBC. Herein, macrophage-camouflaged nanoinducers co-loaded with paclitaxel (PTX) and decitabine (DAC) (P/D-mMSNs) were prepared in combination with PD-1 blockade therapy, hoping to improve the efficacy of chemoimmunotherapy through the demethylation of tumor tissue. Camouflage of macrophage vesicle confers P/D-mMSNs with tumor-homing properties. First, DAC can achieve demethylation of tumor tissue and enhance the sensitivity of tumor cells to PTX. Subsequently, PTX induces immunogenic death of tumor cells, promotes phagocytosis of dead cells by dendritic cells, and recruits cytotoxic T cells to infiltrate tumors. Finally, DAC reverses T cell depletion and facilitates immune checkpoint blockade therapy. P/D-mMSNs may be a promising candidate for future drug delivery design and cancer combination therapy in TNBC.

Self-assembly of CXCR4 antagonist peptide-docetaxel conjugates for breast tumor multi-organ metastasis inhibition

As a representative chemotherapeutic drug, docetaxel (DTX) has been used for breast cancer treatment for decades. However, the poor solubility of DTX limits its efficacy, and the DTX based therapy increases the metastasis risk due to the upregulation of C-X-C chemokine receptor type 4 (CXCR4) expression during the treatment. Herein, we conjugated CXCR4 antagonist peptide (CTCE) with DTX (termed CTCE-DTX) as an anti-metastasis agent to treat breast cancer. CTCE-DTX could self-assemble to nanoparticles, targeting CXCR4-upregulated metastatic tumor cells and enhancing the DTX efficacy. Thus, the CTCE-DTX NPs achieved promising efficacy on inhibiting both bone-specific metastasis and lung metastasis of triple-negative breast cancer. Our work provided a rational strategy on designing peptide-drug conjugates with synergistic anti-tumor efficacy.

Roles of lncRNA in the diagnosis and prognosis of triple-negative breast cancer / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Breast cancer is a malignant tumor that seriously endangers women's lives. The prognosis of breast cancer patients differs among molecular types. Compared with other subtypes, triple-negative breast cancer (TNBC) has been a research hotspot in recent years because of its high degree of malignancy, strong invasiveness, rapid progression, easy of recurrence, distant metastasis, poor prognosis, and high mortality. Many studies have found that long non-coding RNA (lncRNA) plays an important role in the occurrence, proliferation, migration, recurrence, chemotherapy resistance, and other characteristics of TNBC. Some lncRNAs are expected to become biomarkers in the diagnosis and prognosis of TNBC, and even new targets for its treatment. Based on a PubMed literature search, this review summarizes the progress in research on lncRNAs in TNBC and discusses their roles in TNBC diagnosis, prognosis, and chemotherapy with the hope of providing help for future research.

Discovery of a first-in-class ANXA3 degrader for the treatment of triple-negative breast cancer

Triple-negative breast cancer (TNBC) is a nasty disease with extremely high malignancy and poor prognosis. Annexin A3 (ANXA3) is a potential prognosis biomarker, displaying an excellent correlation of ANXA3 overexpression with patients' poor prognosis. Silencing the expression of ANXA3 effectively inhibits the proliferation and metastasis of TNBC, suggesting that ANXA3 can be a promising therapeutic target to treat TNBC. Herein, we report a first-in-class ANXA3-targeted small molecule (R)-SL18, which demonstrated excellent anti-proliferative and anti-invasive activities to TNBC cells. (R)-SL18 directly bound to ANXA3 and increased its ubiquitination, thereby inducing ANXA3 degradation with moderate family selectivity. Importantly, (R)-SL18 showed a safe and effective therapeutic potency in a high ANXA3-expressing TNBC patient-derived xenograft model. Furthermore, (R)-SL18 could reduce the β-catenin level, and accordingly inhibit the Wnt/β-catenin signaling pathway in TNBC cells. Collectively, our data suggested that targeting degradation of ANXA3 by (R)-SL18 possesses the potential to treat TNBC.

Silencing RAB27a inhibits proliferation, invasion and adhesion of triple-negative breast cancer cells / 南方医科大学学报

OBJECTIVE@#To investigate the effect of inhibition of RAB27 protein family, which plays a pivotal role in exosome secretion, on biological behaviors of triple-negative breast cancer cells.@*METHODS@#Quantitative real-time PCR and Western blotting were used to examine the expressions of RAB27 family and exosome secretion in 3 triple-negative breast cancer cell lines (MDA-MB-231, MDA-MB-468, and Hs578T) and a normal breast epithelial cell line (MCF10A). The effect of small interfering RNA (siRNA)-mediated silencing of RAB27a and RAB27b on exosome secretion in the 3 breast cancer cell lines was detected using Western blotting, and the changes in cell proliferation, invasion and adhesion were evaluated.@*RESULTS@#Compared with normal breast epithelial cells, the 3 triple-negative breast cancer cell lines exhibited more active exosome secretion (P < 0.001) and showed significantly higher expressions of RAB27a and RAB27b at both the mRNA and protein levels (P < 0.01). Silencing of RAB27a in the breast cancer cells significantly down-regulated exosome secretion (P < 0.001), while silencing of RAB27b did not significantly affect exosome secretion. The 3 breast cancer cell lines with RAB27a silencing-induced down-regulation of exosome secretion showed obvious inhibition of proliferation, invasion and adhesion (P < 0.01) as compared with the cell lines with RAB27b silencing.@*CONCLUSION@#RAB27a plays central role in the exosome secretion in triple-negative breast cancer cells, and inhibiting RAB27a can inhibit the proliferation, invasion and adhesion of the cells.

Research Progress on Immunization and Targeted Therapy for Triple-negative Breast Cancer / 肿瘤防治研究

Triple-negative breast cancer (TNBC) accounts for approximately 15%–20% of all breast cancers. Patients with TNBC have a rapidly progressive clinical course, an earlier age of onset, faster distant recurrence, and more common visceral metastases as compared with other subtypes. However, treatment of TNBC is often limited to chemotherapy and has a poor prognosis. Therefore, developing the best treatment strategy for patients is essential to reduce the burden of disease caused by TNBC. Various potential available drug targets have been discovered, as well as precision treatment and classified treatment are changing the clinical practice of TNBC, thereby indicating a new therapeutic area for TNBC in addition to traditional chemotherapy. This article reviews the systemic treatment options for TNBC in recent years, including immunotherapy and targeted therapy.

Comparison of Clinicopathological Characteristics Between Primary and Contralateral Cancers in BRCA1/2 Carriers with Metachronous Bilateral Breast Cancers / 肿瘤防治研究

Objective To compare the clinicopathological characteristics between primary and contralateral cancers in patients with metachronous bilateral breast cancer (MBBC) who carried a BRCA1/2 germline pathogenic variant. Methods A total of 496 BRCA1/2 carriers with primary unilateral breast cancer were included (196 with BRCA1 and 300 with BRCA2). Clinicopathological information of patients was collected, and the median follow-up for the entire cohort was 10.4 years (0.4-20.8 years). Results Among all patients, 31 (15.8%) of the 196 BRCA1 carriers and 49 (16.3%) of the 300 BRCA2 carriers had MBBC, respectively. Among the 31 BRCA1 carriers who developed MBBC, the proportion of triple-negative breast cancer (TNBC) in primary cancer and contralateral cancer was 61.3% and 67.7%, respectively. If the primary cancer of BRCA1-mutated MBBC was TNBC, the probability of the contralateral breast cancer with TNBC was 89.5% (17/19), which was significantly higher than that if the primary cancer was non-TNBC (33.3%, 4/12) (P=0.004). Among the 49 BRCA2 carriers who developed MBBC, the predominant molecular phenotype of the primary and contralateral cancers was HR+ & HER2- (77.6% and 67.3%, respectively; P=0.53). Conclusion Approximately 60% of BRCA1 carriers exhibit TNBC. If a BRCA1 carrier with a TNBC primary breast cancer had an MBBC, the probability of the contralateral breast cancer being TNBC phenotype is almost 89.5%.