Tumor-derived extracellular vesicles as a biomarker for breast cancer diagnosis and metastasis monitoring.

It is imperative to explore biomarkers that are both precise and readily accessible in the comprehensive management of breast cancer. A multicenter cohort, including 512 breast cancer patients and 198 nonneoplastic individuals, was recruited to detect the level of tumor-derived extracellular vesicles using our method based on dual DNA tetrahedral nanostructures. The level of tumor-derived extracellular vesicles was significantly higher in newly diagnosed breast cancer patients than in nonneoplastic individuals at a cutoff value of 3.58 U/µL. For postoperative metastasis monitoring, the level of tumor-derived extracellular vesicles was significantly higher in breast cancer patients with metastasis than in those without metastasis at a cutoff value of 3.91 U/µL. Its efficacy of diagnosis and metastasis monitoring was superior to traditional tumor markers. Elevated level of tumor-derived extracellular vesicles served as a predictive biomarker for diagnosis and metastasis monitoring in breast cancer patients.

Cross-talk of Three Molecular Subtypes of Telomere Maintenance Defines Clinical Characteristics and Tumor Microenvironment in Gastric Cancer.

Background: Telomere maintenance takes part in the regulation of gastric cancer (GC) pathogenesis and is essential for patients' clinical features. Though the correlation between a single telomere maintenance-related gene and GC has previously been published, comprehensive exploration and systematic analysis remain to be studied. Our study is aimed at determining telomere maintenance-related molecular subtypes and examining their role in GC. Methods: By analyzing the transcriptome data, we identified three telomere maintenance-associated clusters (TMCs) with heterogeneity in clinical features and tumor microenvironment (TME). Then, we screened five prognostic telomere maintenance-related genes and established corresponding TM scores. Additionally, the expression level and biological function of tubulin beta 6 class V (TUBB6) were validated in GC tissues and cells. Results: TMC1 was correlated with EMT and TGF-beta pathway and predicted low tumor mutation burden (TMB) as well as bad prognostic outcomes. TMC3 was associated with cell cycle and DNA repair. In terms of TMB and overall survival, TMC3 exhibited opposite results against TMC1. Significant heterogeneity was observed between TMCs. TUBB6 was upregulated and could promote GC proliferation, migration, and invasion. Conclusion: Altogether, combining bioinformatics and functional experiments, we identified three molecular subtypes based on telomere maintenance-associated genes in GC, which could bring new ideas and novel biomarkers to the clinic.

Roles of estrogen receptors during sexual reversal in Pelodiscus sinensis.

BACKGROUND: The Chinese soft-shelled turtle, Pelodiscus sinensis, exhibits distinct sexual dimorphism, with the males growing faster and larger than the females. During breeding, all-male offspring can be obtained using 17ß-estradiol (E2). However, the molecular mechanisms underlying E2-induced sexual reversal have not yet been elucidated. Previous studies have investigated the molecular sequence and expression characteristics of estrogen receptors (ERs). METHODS AND RESULTS: In this study, primary liver cells and embryos of P. sinensis were treated with ER agonists or inhibitors. Cell incubation experiments revealed that nuclear ERs (nERs) were the main pathway for the transmission of estrogen signals. Our results showed that ERα agonist (ERα-ag) upregulated the expression of Rspo1, whereas ERα inhibitor (ERα-Inh) downregulated its expression. The expression of Dmrt1 was enhanced after ERα-Inh + G-ag treatment, indicating that the regulation of male genes may not act through a single estrogen receptor, but a combination of ERs. In embryos, only the ERα-ag remarkably promoted the expression levels of Rspo1, Wnt4, and ß-catenin, whereas the ERα-Inh had a suppressive effect. Additionally, Dmrt1, Amh, and Sox9 expression levels were downregulated after ERß inhibitor (ERß-Inh) treatment. GPER agonist (G-ag) has a significant promotion effect on Rspo1, Wnt4, and ß-catenin, while the inhibitor G-Inh does not affect male-related genes. CONCLUSIONS: Overall, these results suggest that ERs play different roles during sexual reversal in P. sinensis and ERα may be the main carrier of estrogen-induced sexual reversal in P. sinensis. Further studies need to be performed to analyze the mechanism of ER action.

Hypoxia stimulates CTC-platelet cluster formation to promote breast cancer metastasis.

Circulating tumor cell clusters/micro-emboli (CTM) possess greater metastatic capacity and survival advantage compared to individual circulating tumor cell (CTC). However, the formation of CTM subtypes and their role in tumor metastasis remain unclear. In this study, we used a microfluidic Cluster-Chip with easy operation and high efficiency to isolate CTM from peripheral blood, which confirmed their correlation with clinicopathological features and identified the critical role of CTC-platelet clusters in breast cancer metastasis. The correlation between platelets and CTM function was further confirmed in a mouse model and RNA sequencing of CTM identified high-expressed genes related to hypoxia stimulation and platelet activation which possibly suggested the correlation of hypoxia and CTC-platelet cluster formation. In conclusion, we successfully developed the Cluster-Chip platform to realize the clinical capture of CTMs and analyze the biological properties of CTC-platelet clusters, which could benefit the design of potential treatment regimens to prevent CTM-mediated metastasis and tumor malignant progression.

Novel Covalent Probe Selectively Targeting Glutathione Peroxidase 4 In Vivo: Potential Applications in Pancreatic Cancer Therapy.

Glutathione peroxidase 4 (GPX4) emerges as a promising target for the treatment of therapy-resistant cancer through ferroptosis. Thus, there is a broad interest in the development of GPX4 inhibitors. However, a majority of reported GPX4 inhibitors utilize chloroacetamide as a reactive electrophilic warhead, and the selectivity and pharmacokinetic properties still need to be improved. Herein, we developed a compound library based on a novel electrophilic warhead, the sulfonyl ynamide, and executed phenotypic screening against pancreatic cancer cell lines. Notably, one compound A16 exhibiting potent cell toxicity was identified. Further chemical proteomics investigations have demonstrated that A16 specifically targets GPX4 under both in situ and in vivo conditions, inducing ferroptosis. Importantly, A16 exhibited superior selectivity and potency compared to reported GPX4 inhibitors, ML210 and ML162. This provides the structural diversity of tool probes for unraveling the fundamental biology of GPX4 and exploring the therapeutic potential of pancreatic cancer via ferroptosis induction.

Estrogen receptor beta suppresses the androgen receptor oncogenic effects in triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer associated with poor prognosis and limited treatment options. The androgen receptor (AR) has emerged as a potential therapeutic target for luminal androgen receptor (LAR) TNBC. However, multiple studies have claimed that anti-androgen therapy for AR-positive TNBC only has limited clinical benefits. This study aimed to investigate the role of AR in TNBC and its detailed mechanism. METHODS: Immunohistochemistry and TNBC tissue sections were applied to investigate AR and nectin cell adhesion molecule 4 (NECTIN4) expression in TNBC tissues. Then, in vitro and in vivo assays were used to explore the function of AR and estrogen receptor beta (ERß) in TNBC. Chromatin immunoprecipitation sequencing (ChIP-seq), co-immunoprecipitation (co-IP), molecular docking method, and luciferase reporter assay were performed to identify key molecules that affect the function of AR. RESULTS: Based on the TNBC tissue array analysis, we revealed that ERß and AR were positive in 21.92% (32/146) and 24.66% (36/146) of 146 TNBC samples, respectively, and about 13.70% (20/146) of TNBC patients were ERß positive and AR positive. We further demonstrated the pro-tumoral effects of AR on TNBC cells, however, the oncogenic biology was significantly suppressed when ERß transfection in LAR TNBC cell lines but not in AR-negative TNBC. Mechanistically, we identified that NECTIN4 promoter -42 bp to -28 bp was an AR response element, and that ERß interacted with AR thus impeding the AR-mediated NECTIN4 transcription which promoted epithelial-mesenchymal transition in tumor progression. CONCLUSIONS: This study suggests that ERß functions as a suppressor mediating the effect of AR in TNBC prognosis and cell proliferation. Therefore, our current research facilitates a better understanding of the role and mechanisms of AR in TNBC carcinogenesis.

Multitarget inhibitors/probes that target LRRK2 and AURORA A kinases noncovalently and covalently.

Herein, we report a salicylaldehyde-based, reversible covalent inhibitor (A2) that possesses moderate cellular activity against AURKA with a prolonged residence time and shows significant non-covalent inhibition towards LRRK2. Our results indicated that this multitarget kinase inhibitor may be used as the starting point for future development of more potent, selective and dual-targeting covalent kinase inhibitors against AURKA and LRRK2 for mitophagy.

c-Myc-Targeting PROTAC Based on a TNA-DNA Bivalent Binder for Combination Therapy of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is highly aggressive with a poor clinical prognosis and no targeted therapy. The c-Myc protein is a master transcription factor and a potential therapeutic target for TNBC. In this study, we develop a PROTAC (PROteolysis TArgeting Chimera) based on TNA (threose nucleic acid) and DNA that effectively targets and degrades c-Myc. The TNA aptamer is selected in vitro to bind the c-Myc/Max heterodimer and appended to the E-box DNA sequence to create a high-affinity, biologically stable bivalent binder. The TNA-E box-pomalidomide (TEP) conjugate specifically degrades endogenous c-Myc/Max, inhibits TNBC cell proliferation, and sensitizes TNBC cells to the cyclin-dependent kinase inhibitor palbociclib in vitro. In a mouse TNBC model, combination therapy with TEP and palbociclib potently suppresses tumor growth. This study offers a promising nucleic acid-based PROTAC modality for both chemical biology studies and therapeutic interventions of TNBC.

Development and validation of a risk prediction model for diabetic retinopathy in type 2 diabetic patients.

To establish a risk prediction model and make individualized assessment for the susceptible diabetic retinopathy (DR) population in type 2 diabetic mellitus (T2DM) patients. According to the retrieval strategy, inclusion and exclusion criteria, the relevant meta-analyses on DR risk factors were searched and evaluated. The pooled odds ratio (OR) or relative risk (RR) of each risk factor was obtained and calculated for ß coefficients using logistic regression (LR) model. Besides, an electronic patient-reported outcome questionnaire was developed and 60 cases of DR and non-DR T2DM patients were investigated to validate the developed model. Receiver operating characteristic curve (ROC) was drawn to verify the prediction accuracy of the model. After retrieving, eight meta-analyses with a total of 15,654 cases and 12 risk factors associated with the onset of DR in T2DM, including weight loss surgery, myopia, lipid-lowing drugs, intensive glucose control, course of T2DM, glycated hemoglobin (HbA1c), fasting plasma glucose, hypertension, gender, insulin treatment, residence, and smoking were included for LR modeling. These factors, followed by the respective ß coefficient was bariatric surgery (- 0.942), myopia (- 0.357), lipid-lowering drug follow-up < 3y (- 0.994), lipid-lowering drug follow-up > 3y (- 0.223), course of T2DM (0.174), HbA1c (0.372), fasting plasma glucose (0.223), insulin therapy (0.688), rural residence (0.199), smoking (- 0.083), hypertension (0.405), male (0.548), intensive glycemic control (- 0.400) with constant term α (- 0.949) in the constructed model. The area under receiver operating characteristic curve (AUC) of the model in the external validation was 0.912. An application was presented as an example of use. In conclusion, the risk prediction model of DR is developed, which makes individualized assessment for the susceptible DR population feasible and needs to be further verified with large sample size application.

Circulating Tumor DNA as a Novel Biomarker Optimizing Treatment for Triple Negative Breast Cancer.

Triple-negative breast cancer is a sub-type of clinically and molecularly heterogeneous malignant disease with a worse prognosis and earlier recurrence than HER2-amplified or hormone-receptor positive breast cancer. Because of the lack of personalized therapy, genetic information is essential to early diagnosing, identifying the high risk of recurrence, guiding therapeutic management, and monitoring treatment efficiency. Circulating tumor DNA (ctDNA) is a novel noninvasive, timely, and tumor specified biomarker that reliably reflects the comprehensive tumor genetic profiles. Thus, it holds significant expectations in personalized therapy, including accurate diagnosis, treatment monitoring, and early detection of recurrence of TNBC. In this review, we summarize the results from recent and ongoing ctDNA-based biomarker-driven clinical trials, with respect to ctDNA analysis' predictive role, in adjuvant, neo-adjuvant, and metastatic settings. Collectively, we anticipate that ctDNA will ultimately be integrated into the management of TNBC to foster precise treatment.

Novel n-i CeO2/a-Al2O3 Heterostructure Electrolyte Derived from the Insulator a-Al2O3 for Fuel Cells.

Heterostructure technologies have been regarded as promising methods in the development of electrolytes with high ionic conductivity for low-temperature solid oxide fuel cells (LT-SOFCs). Here, a novel semiconductor/insulator (n-i) heterostructure strategy has been proposed to develop composite electrolytes for LT-SOFCs based on CeO2 and the insulator amorphous alumina (a-Al2O3). The constructed CeO2/a-Al2O3 electrolyte exhibits an ionic conductivity of up to 0.127 S cm-1, and its fuel cell achieves a maximum power density (MPD) of 1017 mW cm-2 with an open-circuit voltage (OCV) of 1.14 V at 550 °C without the short-circuiting problem, suggesting that the introduction of a-Al2O3 can effectively suppress the electron conduction of CeO2. It is found that the potential energy barrier at the heterointerfaces caused by the ultrawide band gap of the insulator a-Al2O3 plays an important role in restraining electron conduction. Simultaneously, the thermoelectric effect of the insulator induces more oxygen vacancies because of interface charge compensation, which further promotes ionic transport and results in high ionic conductivity and fuel cell performance. This study presents a practical n-i heterostructure electrolyte design, and further research confirmed the advanced functionality of the CeO2/a-Al2O3 electrolyte. Our study may open frontiers in the field of developing high-efficiency electrolytes of LT-SOFCs using insulating materials such as amorphous alumina.

Inhibition of MYC suppresses programmed cell death ligand-1 expression and enhances immunotherapy in triple-negative breast cancer.

BACKGROUND: Cancer immunotherapy has emerged as a promising strategy against triple-negative breast cancer (TNBC). One of the immunosuppressive pathways involves programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1), but many patients derived little benefit from PD-1/PD-L1 checkpoint blockades treatment. Prior research has shown that MYC, a master transcription amplifier highly expressed in TNBC cells, can regulate the tumor immune microenvironment and constrain the efficacy of immunotherapy. This study aims to investigate the regulatory relationship between MYC and PD-L1, and whether a cyclin-dependent kinase (CDK) inhibitor that inhibits MYC expression in combination with anti-PD-L1 antibodies can enhance the response to immunotherapy. METHODS: Public databases and TNBC tissue microarrays were used to study the correlation between MYC and PD-L1. The expression of MYC and PD-L1 in TNBCs was examined by quantitative real-time polymerase chain reaction and Western blotting. A patient-derived tumor xenograft (PDTX) model was used to evaluate the influence of a CDK7 inhibitor THZ1 on PD-L1 expression. Cell proliferation and migration were detected by 5-ethynyl-2'-deoxyuridine (EdU) cell proliferation and cell migration assays. Tumor xenograft models were established for in vivo verification. RESULTS: A high MYC expression level was associated with a poor prognosis and could alter the proportion of tumor-infiltrating immune cells (TIICs). The positive correlation between MYC and PD-L1 was confirmed by immunostaining samples from 165 TNBC patients. Suppression of MYC in TNBC caused a reduction in the levels of both PD-L1 messenger RNA and protein. In addition, antitumor immune response was enhanced in the TNBC cancer xenograft mouse model with suppression of MYC by CDK7 inhibitor THZ1. CONCLUSIONS: The combined therapy of CDK7 inhibitor THZ1 and anti-PD-L1 antibody appeared to have a synergistic effect, which might offer new insight for enhancing immunotherapy in TNBC.

Circulating Tumor Cells and Breast Cancer Metastasis: From Enumeration to Somatic Mutational Profile.

Aims: This study investigates the association between circulating tumor cells (CTCs) and breast cancer metastasis. Methods: A retrospective study was conducted using patients with histologically confirmed breast cancer recruited from the First Affiliated Hospital of Nanjing Medical University during the period of August 2017−October 2020. We used adjusted logistic regression, the random forest algorithm, and sensitivity analysis to study the association between CTC enumeration and tumor metastasis. Further, we performed next-generation sequencing (NGS) on the CTCs obtained from two patients with breast cancer brain metastasis. Results: A total of 41 out of 116 enrolled patients were identified with tumor metastasis. CTC enumeration was significantly higher in patients with liver metastasis than in those without liver metastasis. Patients with CTCs ≥ 5 exhibited a higher risk of tumor metastasis than those with CTCs < 5 in the adjusted model (odds ratios (OR) = 6.25, 95% confidence interval (CI) = 2.63−15.58). The random forest model identified CTC enumeration as a significant metastasis-related variable with the highest mean decrease accuracy and mean decrease Gini score. No significant association was found between CTCs and visceral metastasis with an OR of 1.29 (95% CI = 0.98−2.05, p = 0.232). Upon further investigating organ-specific metastasis, we found that patients with high CTC levels were more likely to develop liver metastasis (OR = 4.87, 95% CI = 1.34−20.17, p = 0.021). The NGS study of CTCs identified a total of 120 indel mutations (e.g., CNGB1, NTSR1, ZG16). The enriched biological processes were mechanoreceptor differentiation and macrophage activation involved in the immune response. The enriched KEGG pathways included focal adhesion, the PI3K-Akt signaling pathway, and microRNAs involved in cancer. Conclusions: Our study revealed that CTCs ≥ 5 are a risk factor for tumor metastasis in breast cancer patients. In addition, we reported that CTCs ≥ 5 might be associated with a higher risk of liver metastasis in patients with metastatic breast cancer. We have provided the mutational profiles of CTCs based on next-generation sequencing.

Discovery of 8-(6-Methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1,5-dihydro-4H-[1,2,3]triazolo[4,5-c]quinolin-4-one (CQ211) as a Highly Potent and Selective RIOK2 Inhibitor.

RIOK2 is an atypical kinase implicated in multiple human cancers. Although recent studies establish the role of RIOK2 in ribosome maturation and cell cycle progression, its biological functions remain poorly elucidated, hindering the potential to explore RIOK2 as a therapeutic target. Here, we report the discovery of CQ211, the most potent and selective RIOK2 inhibitor reported so far. CQ211 displays a high binding affinity (Kd = 6.1 nM) and shows excellent selectivity to RIOK2 in both enzymatic and cellular studies. It also exhibits potent proliferation inhibition activity against multiple cancer cell lines and demonstrates promising in vivo efficacy in mouse xenograft models. The crystal structure of RIOK2-CQ211 sheds light on the molecular mechanism of inhibition and informs the subsequent optimization. The study provides a cell-active chemical probe for verifying RIOK2 functions, which may also serve as a leading molecule in the development of therapeutic RIOK2 inhibitors.

Cell-Active, Reversible, and Irreversible Covalent Inhibitors That Selectively Target the Catalytic Lysine of BCR-ABL Kinase.

Despite recent interests in developing lysine-targeting covalent inhibitors, no general approach is available to create such compounds. We report herein a general approach to develop cell-active covalent inhibitors of protein kinases by targeting the conserved catalytic lysine residue using key SuFEx and salicylaldehyde-based imine chemistries. We validated the strategy by successfully developing (irreversible and reversible) covalent inhibitors against BCR-ABL kinase. Our lead compounds showed high levels of selectivity in biochemical assays, exhibited nanomolar potency against endogenous ABL kinase in cellular assays, and were active against most drug-resistant ABL mutations. Among them, the salicylaldehyde-containing A5 is the first-ever reversible covalent ABL inhibitor that possessed time-dependent ABL inhibition with prolonged residence time and few cellular off-targets in K562 cells. Bioinformatics further suggested the generality of our strategy against the human kinome.

Associations of SMAD4 rs10502913 and NLRP3 rs1539019 Polymorphisms with Risk of Coal Workers' Pneumoconiosis Susceptibility in Chinese Han Population.

Purpose: CWP is an untreatable but preventable fibrotic lung disease caused by the chronic inhalation of coal dust. Genetic factors such as polymorphisms play an important role in the development of CWP. The present study investigated the association between the polymorphisms of SMAD4 and NLRP3 and CWP risk in a Chinese Han population. Patients and Methods: SMAD4 rs10502913 and NLRP3rs1539019 polymorphisms were examined in 292 CWP subjects and 315 coal dust-exposed controls. The genotypes were analyzed using direct sequencing. The allele and genotype proportion between the cases and controls were compared using the chi-square test. Results: The AG and GG genotypes of SMAD4 rs10502913 were not associated with altered CWP risk compared with AA genotype (adjusted OR = 1.535 and 1.426, 95% CI = 0.785-3.000 and 0.732-2.781, p = 0.210 and 0.297, respectively). Also, the NLRP3 rs1539019 heterozygous and homozygous variants CA and CC genotypes were not associated with the risk of CWP compared with the AA genotype (adjusted OR = 0.985 and 1.127, 95% CI = 0.652-1.489 and 0.713-1.782, p = 0.944 and 0.608, respectively). In addition, there was no interaction between SMAD4 rs10502913 and NLRP3 rs1539019 genotypes and smoking status on CWP risk in the stratified analyses. Conclusion: In this present study, SMAD4 rs10502913 and NLRP3 rs1539019 genotypes were not associated with altered CWP risk in the Chinese Han population. Large sample sizes and multicenter studies are needed to elucidate these results in the future.

Secondary-structure switch regulates the substrate binding of a YopJ family acetyltransferase.

The Yersinia outer protein J (YopJ) family effectors are widely deployed through the type III secretion system by both plant and animal pathogens. As non-canonical acetyltransferases, the enzymatic activities of YopJ family effectors are allosterically activated by the eukaryote-specific ligand inositol hexaphosphate (InsP6). However, the underpinning molecular mechanism remains undefined. Here we present the crystal structure of apo-PopP2, a YopJ family member secreted by the plant pathogen Ralstonia solanacearum. Structural comparison of apo-PopP2 with the InsP6-bound PopP2 reveals a substantial conformational readjustment centered in the substrate-binding site. Combining biochemical and computational analyses, we further identify a mechanism by which the association of InsP6 with PopP2 induces an α-helix-to-ß-strand transition in the catalytic core, resulting in stabilization of the substrate recognition helix in the target protein binding site. Together, our study uncovers the molecular basis governing InsP6-mediated allosteric regulation of YopJ family acetyltransferases and further expands the paradigm of fold-switching proteins.

Single-cell RNA sequencing reveals cell heterogeneity and transcriptome profile of breast cancer lymph node metastasis.

Molecular mechanisms underlying breast cancer lymph node metastasis remain unclear. Using single-cell sequencing, we investigated the transcriptome profile of 96,796 single cells from 15 paired samples of primary tumors and axillary lymph nodes. We identified nine cancer cell subclusters including CD44 + / ALDH2 + /ALDH6A1 + breast cancer stem cells (BCSCs), which had a copy-number variants profile similar to that of normal breast tissue. Importantly, BCSCs existed only in primary tumors and evolved into metastatic clusters infiltrating into lymph nodes. Furthermore, transcriptome data suggested that NECTIN2-TIGIT-mediated interactions between metastatic breast cancer cells and tumor microenvironment (TME) cells, which promoted immune escape and lymph node metastasis. This study is the first to delineate the transcriptome profile of breast cancer lymph node metastasis using single-cell RNA sequencing. Our findings offer novel insights into the mechanisms underlying breast cancer metastasis and have implications in developing novel therapies to inhibit the initiation of breast cancer metastasis.

Novel Electrophilic Warhead Targeting a Triple-Negative Breast Cancer Driver in Live Cells Revealed by "Inverse Drug Discovery".

The "inverse drug discovery" strategy is a potent means of exploring the cellular targets of latent electrophiles not typically used in medicinal chemistry. Cyclopropenone, a powerful electrophile, is generally used in bio-orthogonal reactions mediated by triarylphosphine or in photo-triggered cycloaddition reactions. Here, we have studied, for the first time, the proteome reactivity of cyclopropenones in live cells and discovered that the cyclopropenone warhead can specifically and efficiently modify a triple-negative breast cancer driver, glutathione S-transferase pi-1 (GSTP1), by covalently binding at the catalytic active site. Further structure optimization and signaling pathway validation have led to the discovery of potent inhibitors of GSTP1.

Heterogeneity of CTC contributes to the organotropism of breast cancer.

Circulating tumor cells (CTCs) are viewed as pro-metastasis precursors shed from primary tumors or metastatic sites. The phenotypic and molecular heterogeneity of CTCs is associated with breast cancer progression and prognosis. Therefore, we divided CTCs into several subtypes according to their differences in biomarker status, epithelial/mesenchymal phenotype, aggregation status, and other factors to summarize their characteristics. Considering that the organ-specific metastasis is a hallmark of breast cancer, we adopted the "seed and soil" model to further analyze the relationship between the heterogeneity of CTCs and the organotropism of breast cancer. We speculated that CTCs might not only develop their genetic potential but communicate with surroundings, including chemokine systems, hemocytes, and extracellular matrix components, to regulate the organ-specific metastases of breast cancer.