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Breast cancer is marked by large increases in the protein fibers around tumor cells. These fibers increase the mechanical stiffness of the tissue, which has long been used for tumor diagnosis by manual palpation. Recent research in bioengineering has led to the development of novel biomaterials that model the mechanical and architectural properties of the tumor microenvironment and can be used to understand how these cues regulate the growth and spread of breast cancer. Herein, we provide an overview of how the mechanical properties of breast tumor tissues differ from those of normal breast tissue and non-cancerous lesions. We also describe how biomaterial models make it possible to understand how the stiffness and viscosity of the extracellular environment regulate cell migration and breast cancer metastasis. We highlight the need for biomaterial models that allow independent analysis of the individual and different mechanical properties of the tumor microenvironment and that use cells derived from different regions within tumors. These models will guide the development of novel mechano-based therapies against breast cancer metastasis.

Breast cancer is one of the most common malignancies in women. It frequently metastasizes to the lungs, liver, and bone. Breast cancer metastasis to skeletal muscles is rare. Chest wall recurrence in patients that have undergone mastectomy is the most frequent form of local recurrence, and it is generally accompanied by nodules or masses on the chest wall. Here, we describe a case of the unusual appearance of invasive lobular cancer metastasis to the pectoral muscles without discrete nodules or masses in a patient who had undergone mastectomy 12 years ago.

The tumor-to-tumor metastasis phenomenon remains fairly uncommon, with fewer than 100 cases described to present time. Virtually any tumor can be a donor or a recipient neoplasm. Nevertheless, renal carcinomas have been implicated as the most common malignant tumors to harbor metastasis, while lung and breast tumors are the most frequent donors. This article reports an extremely rare case of a breast cancer metastasis in a lung metastasis of clear cell type renal cell carcinoma that met all Campbell and coworkers’ tumor-to-tumor metastasis criteria. Additionally, we present the literature case reports of breast cancer metastasis in renal cell carcinomas and try to discuss the mechanisms underlying its occurrence. Since this phenomenon identification will impact the therapeutic strategy and it is not easily detected by image, the anatomopathological study of any and all suspicious lesions is of crucial importance. To the best of our knowledge, this is the first report of a metastasis inside a metastasis.

Breast cancer metastasis and recurrence accounts for vast majority of breast cancer-induced mortality. Tumor microenvironment (TME) plays an important role at each step of metastasis, evasion of immunosurveillance, and therapeutic resistance. Consequently, TME-targeting alternatives to traditional therapies focused on breast cancer cells are gaining increasing attention. These new therapies involve the use of tumor cells, and key TME components or secreted bioactive molecules as therapeutic targets, alone or in combination. Recently, TME-related nanoparticles have been developed to deliver various agents, such as bioactive ingredients extracted from natural sources or chemotherapeutic agents, genes, proteins, small interfering RNAs, and vaccines; they have shown great therapeutic potential against breast cancer metastasis. Among various types of nanoparticles, biomimetic nanovesicles are a promising means of addressing the limitations of conventional nanocarriers. This review highlights various nanoparticles related to or mediated by TME according to the key TME components responsible for metastasis. Furthermore, TME-related biomimetic nanoparticles against breast cancer metastasis have garnered attention owing to their promising efficiency, especially in payload delivery and therapeutic action. Here, we summarize recent representative studies on nanoparticles related to cancer-associated fibroblasts, extracellular matrix, endothelial cells, angiogenesis, and immune cells, as well as advanced biomimetic nanoparticles. Future challenges and opportunities in the field are also discussed.

The bioprinting technique with specialized tissue production allows the study of biological, physiological, and behavioral changes of cancerous and non-cancerous tissues in response to pharmacological compounds in personalized medicine. To this end, to evaluate the efficacy of anticancer drugs before entering the clinical setting, tissue engineered 3D scaffolds containing breast cancer and derived from the especially patient, similar to the original tissue architecture, can potentially be used. Despite recent advances in the manufacturing of 3D bioprinted breast cancer tissue (BCT), many studies still suffer from reproducibility primarily because of the uncertainty of the materials used in the scaffolds and lack of printing methods. In this review, we present an overview of the breast cancer environment to optimize personalized treatment by examining and identifying the physiological and biological factors that mimic BCT. We also surveyed the materials and techniques related to 3D bioprinting, i.e, 3D bioprinting systems, current strategies for fabrication of 3D bioprinting tissues, cell adhesion and migration in 3D bioprinted BCT, and 3D bioprinted breast cancer metastasis models. Finally, we emphasized on the prospective future applications of 3D bioprinted cancer models for rapid and accurate drug screening in breast cancer.

Breast cancer (BC) is the most frequently invasive malignancy and the leading cause of tumor-related mortality among women worldwide. Cancer metastasis is a complex, multistage process, which eventually causes tumor cells to colonize and grow at the metastatic site. Distant organ metastases are the major obstacles to the management of advanced BC patients. Notably, exosomes are defined as specialized membrane-enclosed extracellular vesicles with specific biomarkers, which are found in a wide variety of body fluids. Recent studies have demonstrated that exosomes are essential mediators in shaping the tumor microenvironment and BC metastasis. The transferred tumor-derived exosomes modify the capability of invasive behavior and organ-specific metastasis in recipient cells. BC exosomal components, mainly including noncoding RNAs (ncRNAs), proteins, lipids, are the most investigated components in BC metastasis. In this review, we have emphasized the multifaceted roles and mechanisms of tumor-derived exosomes in BC metastasis based on these important components. The underlying mechanisms mainly include the invasion behavior change, tumor vascularization, the disruption of the vascular barrier, and the colonization of the targeted organ. Understanding the significance of tumor-derived exosomal components in BC metastasis is critical for yielding novel routes of BC intervention.

Breast cancer metastasis to unusual locations may present as a diagnostic challenge. Recognizing the different manifestations of metastatic breast disease can help to guide patient treatment and assist in disease prognosis. The purpose of this article is to illustrate the imaging findings of some of the unusual or infrequent locations of breast metastases through a series of interesting cases and to revisit this uncommon clinical issue.

A patient with intrahepatic breast cancer metastasis underwent both 18F-FDG and 68Ga-FAPI PET/CT. However, the lesions are only 68Ga-FAPI avid. Our case illustrates that 68Ga-FAPI PET/CT can be more sensitive in detecting intrahepatic metastasis of breast cancer in some cases.

This case report takes readers through our journey to a diagnosis of a breast cancer metastasis superimposed on a stage II MRONJ lesion. It highlights the importance of sending all bone sequestra excised intraoperatively for histopathological examination.

Breast cancer bone metastasis poses significant challenge for therapeutic strategies. Inside the metastatic environment, osteoclasts and tumor cells interact synergistically to promote cancer progression. In this study, the proprotein convertase furin is targeted due to its critical roles in both tumor cell invasion and osteoclast function. Importantly, the furin inhibitor is specifically delivered by bone targeting superparamagnetic iron oxide (SPIO) nanoparticles. Our in vitro and in vivo data demonstrate that this system can effectively inhibit both osteoclastic bone resorption and breast cancer invastion, leading to alleviated osteolysis. Therefore, the bone targeting & furin inhibition nanoparticle system is a promising therapeutic and diagnostic strategy for breast cancer bone metastasis., Graphical abstract Image 1, Highlights • A bone targeting delivery system is synthesized for the treatment of breast cancer bone metastasis. • When delivered to bone, peptides that can inhibit furin to inhibit both breast cancer cells and bone destructive osteoclasts. • This system is proved to be effective in protect breast cancer associated osteolysis in vivo.

Metastatic disease to the liver is a known and common site of breast cancer spread, classically presenting as either hypovascular or hypervascular masses. Rarely, hepatic metastatic disease may have an atypical diffuse and intrasinusoidal pattern of involvement, which may be radiographically occult or extremely challenging to diagnose even with multiphase contrast enhanced techniques. We report a case of a 28-year-old female with stage III invasive ductal carcinoma of the breast, who recently discontinued treatment due to pregnancy, presenting with progressive signs and symptoms of rapidly decompensating liver failure due to sinusoidal obstruction. Multimodality imaging was performed without evidence for focal hepatic metastatic disease; however, intrahepatic vein (IVC) compression was noted. Hepatic sinusoidal tumor infiltration was confirmed by liver biopsy. After palliative chemotherapy the disease became less infiltrative and more conspicuous on imaging, revealing itself as hepatic metastases, with decreased compression of the intrahepatic IVC and resolution of signs and symptoms of sinusoidal obstruction syndrome.

Cancer growth is usually accompanied by metastasis which kills most cancer patients. Here we aim to study the effect of cisplatin at different doses on breast cancer growth and metastasis. Methods: We used cisplatin to treat breast cancer cells, then detected the migration of cells and the changes of epithelial-mesenchymal transition (EMT) markers by migration assay, Western blot, and immunofluorescent staining. Next, we analyzed the changes of RNA expression of genes by RNA-seq and confirmed the binding of activating transcription factor 3 (ATF3) to cytoskeleton related genes by ChIP-seq. Thereafter, we combined cisplatin and paclitaxel in a neoadjuvant setting to treat xenograft mouse models. Furthermore, we analyzed the association of disease prognosis with cytoskeletal genes and ATF3 by clinical data analysis. Results: When administered at a higher dose (6 mg/kg), cisplatin inhibits both cancer growth and metastasis, yet with strong side effects, whereas a lower dose (2 mg/kg) cisplatin blocks cancer metastasis without obvious killing effects. Cisplatin inhibits cancer metastasis through blocking early steps of EMT. It antagonizes transforming growth factor beta (TGFβ) signaling through suppressing transcription of many genes involved in cytoskeleton reorganization and filopodia formation which occur early in EMT and are responsible for cancer metastasis. Mechanistically, TGFβ and fibronectin-1 (FN1) constitute a positive reciprocal regulation loop that is critical for activating TGFβ/SMAD3 signaling, which is repressed by cisplatin induced expression of ATF3. Furthermore, neoadjuvant administration of cisplatin at 2 mg/kg in conjunction with paclitaxel inhibits cancer growth and blocks metastasis without causing obvious side effects by inhibiting colonization of cancer cells in the target organs. Conclusion: Thus, cisplatin prevents breast cancer metastasis through blocking early EMT, and the combination of cisplatin and paclitaxel represents a promising therapy for killing breast cancer and blocking tumor metastasis.

Facial nerve (FN) palsy, as a solitary symptom, resulting from metastatic tumor is not frequent. In this article, we report an unusual case of the breast cancer metastasis to the labyrinthine segment of a facial nerve.

Objective Breast cancer is one of the most important public health problems among women worldwide. It is a major cause of morbidity especially among women in developing countries including Thailand. The purpose of this study was to study the expression of LPHN3 protein in normal breast tissue compared to breast cancer tissue. Methods We had studied the expression of LPHN3 in 65 breast tissues using an immunohistochemistry method. The association between LPHN3 expression and breast cancer metastasis to nearby axillary lymph nodes was also examined. Results Among the 65 breast cancer and normal breast tissues examined, LPHN3 expression with an immunohistochemistry index (IHC index) greater than 4 was more frequently found in breast cancer tissues than in normal breast tissues (P-value = 0.001, OR (95% CI) = 7.04 (2.16-23)). Moreover, a high expression of LPHN3 (IHC index > 4) was more frequently found in breast cancer tissues with negative axillary lymph nodes than in those with positive ones (P-value = 0.038, OR (95% CI) = 0.25 (0.07-0.96)). LPHN3 protein might be a new metastasis suppressor gene in breast cancer and a marker for breast cancer metastasis prevention. Conclusions The present study indicated that a decrease of LPHN3 protein expression in breast cancer tissue might be a marker indicating the aggressiveness of breast cancer. These results also suggested that a decrease of LPHN3 expression could be functionally involved in breast cancer progression and metastasis.

Purpose In daily practice, a contralateral breast cancer (CBC) is usually considered as a new independent tumor despite the indications of several studies showing that the second neoplasia may be a metastatic spread of the primary tumor. Recognition of clonal masses in the context of multiple synchronous or metachronous tumors is crucial for correct prognosis, therapeutic choice, and patient management. Mitochondrial DNA (mtDNA) sequencing shows high informative potential in the diagnosis of synchronous neoplasms, based on the fact that somatic mtDNA mutations are non-recurrent events, whereas tumors sharing them have a common origin. We here applied this technique to reveal clonality of the CBC with respect to the first tumor. Methods We analyzed 30 sample pairs of primary breast cancers and synchronous or metachronous CBCs with detailed clinical information available and compared standard clinico-pathological criteria with mtDNA sequencing to reveal the metastatic nature of CBCs. Results MtDNA analysis was informative in 23% of the cases, for which it confirmed a clonal origin of the second tumor. In addition, it allowed to solve two ambiguous cases where histopathological criteria had failed to be conclusive and to suggest a clonal origin for two additional cases that had been classified as independent by pathologists. Conclusion Overall, the mtDNA-based classification showed a more accurate predictive power than standard histopathology in identifying cases of metastatic rather than bilateral breast cancers in our cohort, suggesting that mtDNA sequencing may be a more precise and easy-to-use method to be introduced in daily routine to support and improve histopathological diagnoses.

Besides its well‐known benefits on human health, calcitriol, the hormonally active form of vitamin D3, has been being evaluated in clinical trials as an anticancer agent. However, currently available results are contradictory and not fundamentally deciphered. To the best of our knowledge, hypercalcemia caused by high‐dose calcitriol administration and its low bioavailability limit its anticancer investigations and translations. Here, we show that the one‐step self‐assembly of calcitriol and amphiphilic cholesterol‐based conjugates leads to the formation of a stable minimalist micellar nanosystem. When administered to mice, this nanosystem demonstrates high calcitriol doses in breast tumor cells, significant tumor growth inhibition and antimetastasis capability, as well as good biocompatibility. We further reveal that the underlying molecular antimetastatic mechanisms involve downregulation of proteins facilitating metastasis and upregulation of paxillin, the key protein of focal adhesion, in primary tumors.

ER(+) breast cancer exhibits a strong bone-tropism in metastasis. How the bone microenvironment (BME) impacts ER signaling and endocrine therapy remains poorly understood. Here, we discover that the osteogenic niche transiently and reversibly reduces ER expression and activities specifically in BMMs, leading to endocrine resistance. As bone micrometastases (BMMs) progress, the ER reduction and endocrine resistance may partially recover in cancer cells away from the osteogenic niche, creating phenotypic heterogeneity in macrometastases. Using multiple approaches including an evolving barcoding strategy, we demonstrated that this process is independent of clonal selection, and represents an EZH2-mediated epigenomic reprogramming. EZH2 drives ER(+) BMMs toward a basal and stem-like state. EZH2 inhibition reverses endocrine resistance. These data exemplify how epigenomic adaptation to BME promotes phenotypic plasticity of metastatic seeds, fosters intra-metastatic heterogeneity, and alters therapeutic responses. Our study provides insights into the clinical enigma of ER+ metastatic recurrences despite endocrine therapies.

The liver is one of the most common sites of breast cancer metastasis and is associated with high lethality. Although the interaction between tumor cells and their microenvironment at metastatic sites has been recognized as a key regulator of tumor progression, the underlying mechanism is not fully elucidated. Here, we describe a three-dimensional (3D) microfluidic human liver-on-a-chip (liver-chip) that emulates the formation of a premetastatic niche to investigate the roles of breast cancer-derived extracellular vesicles (EVs) in liver metastasis. We demonstrate that breast cancer-derived EVs activate liver sinusoidal endothelial cells (LSECs) in the liver-chip, inducing endothelial to mesenchymal transition and destruction of vessel barriers. In addition, we show that transforming growth factor β1 (TGFβ1) in breast cancer-derived EVs upregulates fibronectin, an adhesive extracellular matrix protein, on LSECs, which facilitates the adhesion of breast cancer cells to the liver microenvironment. Furthermore, we observed that EVs isolated from triple-negative breast cancer (TNBC) patients with liver metastasis contain higher TGFβ1 levels and induce adhesion of more breast cancer cells to the 3D human liver-chip than do EVs isolated from healthy donors or nonmetastatic TNBC patients. These findings provide a better understanding of the mechanisms through which breast cancer-derived EVs guide secondary metastasis to the liver. Furthermore, the 3D human liver-chip described in this study provides a platform to investigate the mechanisms underlying secondary metastasis to the liver and possible therapeutic strategies.

The most common site of breast cancer metastasis is the bone, occurring in approximately 70% of patients with advanced disease. Bone metastasis is associated with severe morbidities and high mortality. Therefore, deeper understanding of the mechanisms that enable bone-metastatic relapse are urgently needed. We report the establishment and characterization of a bone-seeking variant of breast cancer cells that spontaneously forms aggressive bone metastases following surgical resection of primary tumor. We characterized the modifications in the immune milieu during early and late stages of metastatic relapse and found that the formation of bone metastases is associated with systemic changes, as well as modifications of the bone microenvironment towards an immune suppressive milieu. Furthermore, we characterized the intrinsic changes in breast cancer cells that facilitate bone-tropism and found that they acquire mesenchymal and osteomimetic features. This model provides a clinically relevant platform to study the functional interactions between breast cancer cells and the bone microenvironment, in an effort to identify novel targets for intervention.

Breast cancer is the second leading cause of cancer‐related deaths in women. The long noncoding RNA LINC00115 has been reported to be involved in the poor outcome of patients with breast cancer, but the biological function and underlying mechanism remain unclear. Here, we report that LINC00115 expression is increased in triple‐negative breast cancer tissue compared with matched normal tissue, and LINC00115 knockdown suppresses breast cancer cell migration and invasion. Furthermore, we show that LINC00115 directly targets miR‐7 and inhibits its expression. LINC00115 also reduces the expression of KLF4, which is a direct target of miR‐7 and is involved in breast cancer metastasis. Together, our findings suggest that LINC00115 promotes breast cancer metastasis through modulating the expression of miR‐7 and KLF4., LINC00115 expression is increased in breast cancer tissue and promotes tumor cell migration and invasion by inhibiting miR‐7 expression. This miRNA has been identified as a tumor suppressor in breast cancer, and one of its direct targets, KLF4, is an oncogene in breast cancer.

The solute carrier (SLC) superfamily encompasses a large variety of membrane-bound transporters required to transport a diverse array of substrates over biological membranes. Physiologically, they are essential for nutrient uptake, ion transport and waste removal. However, accumulating evidence suggest that up- and/or downregulation of SLCs may play a pivotal role in the pathogenesis of human malignancy. Endogenous substrates of SLCs include oestrogen and its conjugates, the handling of which may be of importance in hormone-dependent cancers. The SLCs play a significant role in the handling of therapeutic agents including anticancer drugs. Differential SLC expression in cancers may, therefore, impact on the efficacy of treatments. However, there is also a small body of evidence to suggest the dysregulated expression of some of these transporters may be linked to cancer metastasis. This review draws on the current knowledge of the roles of SLC transporters in human cancers in order to highlight the potential significance of these solute carriers in breast cancer pathogenesis and treatment.

An 80-year-old woman with a history of breast cancer 16 years ago presented with malnutrition, swelling, and paresthesia of the right cheek. Computed tomography revealed diffuse osteosclerosis without lysis and adjacent soft tissue swelling on the right mandible. These radiological findings were more compatible with primary chronic osteomyelitis than metastasis from breast cancer, and biopsy was necessary for diagnosis. This report describes breast cancer metastasis mimicking primary chronic osteomyelitis 16 years after diagnosis and its differential diagnosis in the mandible.

Objective Obesity is closely associated with metastasis in breast cancer patients. Secreted frizzled-related protein 5 (SFRP5), one of the novel adipokines with anti-inflammatory properties, is associated with obesity. This study aims to study the role of SFRP5 in the crosstalk between obesity and breast cancer metastasis and identify the underlying mechanism. Methods 3T3-L1 pre-adipocytes were differentiated to mature adipocytes and a hypertrophic adipocyte model was induced with palmitic acid (PA). Cell motility was measured in MDA-MB-231 and MCF-7 breast cancer cells co-cultured with adipocytes conditioned medium (CM) with or without SFRP5 protein. Wnt and epithelial-mesenchymal transition (EMT) signal pathways were investigated by western blot. Circulating SFRP5 level in 218 breast cancer patients and the association with clinicopathologic characteristics of breast cancer were further determined. Online databases ENCORI and PREDICT Plus were used to exam the link between SFRP5 and prognosis. Results Reduced SFRP5 level was detected in the hypertrophic adipocyte model. Recombinant SFRP5 protein inhibited MDA-MB-231 and MCF-7 cells invasion and migration induced by PA-treated adipocyte CM, and SFRP5 inhibition by specific antibody reversed the effect of SFRP5. Furthermore, SFRP5 significantly inhibited Wnt and downstream EMT in breast cancer cells. Low circulating SFRP5 level correlated with body mass index (BMI), lymph node (LN) metastasis, TNM stage and high Ki67 expression in breast cancer patients. Increased SFRP5 level was associated with favorable predicted survival. Kaplan-Meier curves showed high SFRP5 level in tumor tissue was associated with better outcome of breast cancer patients. Conclusions Our findings demonstrated SFRP5 is a vital adipokine that mediates the crosslink between obesity and the metastatic potential of breast cancer. Promotion of SFRP5 expression in the adipose microenvironment may represent a novel approach for preventing breast cancer metastasis.

Cancer-associated fibroblasts (CAFs) are activated fibroblasts that constitute the major components of tumor microenvironment (TME) and play crucial roles in tumor development and metastasis. Here, we generated fibroblast-specific inducible focal adhesion kinase (FAK) knockout (cKO) mice in a breast cancer model to study potential role and mechanisms of FAK signaling in CAF to promote breast cancer metastasis in vivo. While not affecting primary tumor development and growth, FAK deletion significantly suppressed breast cancer metastasis in vivo. Analyses of CAFs derived from cKO mice as well as human CAFs showed that FAK is required for their activity to promote mammary tumor cell migration. We further showed that FAK ablation in CAFs decreased their exosome amount and functions to promote tumor cell migration and other activities, which could contribute to the reduced metastasis observed in cKO mice. Lastly, profiling of miRs from CAF exosomes showed alterations of several exosomal miRs in FAK-null CAFs, and further analysis suggested that miR-16 and miR-148a enriched in exosomes from FAK-null CAFs contribute to the reduced tumor cell activities and metastasis. Together, these results identify a new role for FAK signaling in CAFs that regulate their intercellular communication with tumor cells to promote breast cancer metastasis.

An activatable nanoprobe for imaging breast cancer metastases through near infrared-I (NIR-I)/NIR-II fluorescence imaging and multispectral optoacoustic tomography (MSOT) imaging was designed. With a dihydroxanthene moiety serving as the electron donor, quinolinium as the electron acceptor and nitrobenzyloxydiphenylamino as the recognition element, the probe can specifically respond to nitroreductase and transform into an activated D-π-A structure with a NIR emission band extending beyond 900 nm. The activated nanoprobe exhibits NIR emission enhanced by aggregation-induced emission (AIE) and produces strong optoacoustic signal. The nanoprobe was used to detect and image metastases from the orthotopic breast tumors to lymph nodes and then to lung in two breast cancer mouse models. Moreover, the nanoprobe can monitor the treatment efficacy during chemotherapeutic course through fluorescence and MSOT imaging.

Purpose: The function of long noncoding RNAs (lncRNA) in breast cancer metastasis remains largely unknown. In this work, the role of HOXC-AS3 in breast cancer progression was investigated.Methods: ...

Brain metastases affect one-third of patients with HER2-positive breast cancer. However, solitary pituitary metastases are rare and are often difficult to diagnose. A better understanding of its clinical and radiological manifestations may lead to earlier diagnosis and treatment. Therefore, we present this case report of a patient with a solitary pituitary metastasis, focusing on her diagnosis and treatment.

Simple Summary Intratumoral hypoxia is a negative prognostic factor in breast cancer progression and recurrence. By implementing a hypoxia fate-mapping system, we followed cells that experience intratumoral hypoxia in vivo and determined that these cells have an increased ability to metastasize compared to cells that were never exposed to hypoxia. In this work, we investigate whether cells that experienced intratumoral hypoxia are also resistant to chemotherapy. By utilizing both in vivo and ex vivo models, we conclude that metastatic cells found in the lung and liver, that were exposed to hypoxia in the primary tumor, are less sensitive to doxorubicin and paclitaxel and drive recurrence after treatment. Our studies also suggest that chemoresistance is associated with a cancer stem cell-like phenotype that is maintained in post-hypoxic cells. Abstract Hypoxia occurs in 90% of solid tumors and is associated with treatment failure, relapse, and mortality. HIF-1α signaling promotes resistance to chemotherapy in cancer cell lines and murine models via multiple mechanisms including the enrichment of breast cancer stem cells (BCSCs). In this work, we utilize a hypoxia fate-mapping system to determine whether triple-negative breast cancer (TNBC) cells that experience hypoxia in the primary tumor are resistant to chemotherapy at sites of metastasis. Using two orthotopic mouse models of TNBC, we demonstrate that cells that experience intratumoral hypoxia and metastasize to the lung and liver have decreased sensitivity to doxorubicin and paclitaxel but not cisplatin or 5-FU. Resistance to therapy leads to metastatic recurrence caused by post-hypoxic cells. We further determined that the post-hypoxic cells that metastasize are enriched in pathways related to cancer stem cell gene expression. Overall, our results show that even when hypoxic cancer cells are reoxygenated in the bloodstream they retain a hypoxia-induced cancer stem cell-like phenotype that persists and promotes resistance and eventually recurrence.

Most studies on breast cancer metastasis have been performed using triple-negative breast cancer (TNBC) cells; thus, subtype-dependent metastatic ability of breast cancer is poorly understood. In this research, we performed intravenous injection (IVI) and intra-caudal arterial injections (CAI) using nine human epidermal growth factor receptor-2 (HER2)-positive breast cancer cell lines for evaluating their metastatic abilities. Our results showed that MDA-MB-453, UACC-893, and HCC-202 had strong bone metastatic abilities, whereas HCC-2218 and HCC-1419 did not show bone metastasis. HER2-positive cell lines could hardly metastasize to the lung through IVI. From the genomic analysis, gene signatures were extracted according to the breast cancer subtypes and their metastatic preferences. The UACC-893 cell line was identified as a useful model for the metastasis study of HER2-positive breast cancer. Combined with our previous result on brain proliferation ability, we provide a characteristic metastasis profile of HER2-positive breast cancer cell lines in this study.Statements and DeclarationsFundingThis study was supported by JSPS KAKENHI (grant no. 18K16269: Grant-in-Aid for Early-Career Scientist to J.N.; grant no. 20J01794, Grant-in-Aid for JSPS fellows to J.N.; grant no. 20J23297, Grant-in-Aid for JSPS fellows to Y.H.) and partially supported by the grants for translational research programs from Fukushima Prefecture (S.W. and K.S.).AuthorshipYH and KA performed the in vivo experiments and bioinformatical analyses. SW, and KS interpreted the data. YH, KA, and JN wrote the manuscript. JN conceived and designed the study. All the authors reviewed and edited the manuscript.Competing InterestsThe authors declare that they have no competing interests.Ethical approvalThe animal experiments were conducted under the approval of the ethics committee of Waseda University (2020-A067, 2021-A074).

Breast cancer is an aggressive silent disease, representing 11.7% of the diagnosed cancer worldwide, and it is also a leading cause of death in Saudi Arabia. Consequently, microRNAs have emerged recently as potential biomarkers to diagnose and monitor such cases at the molecular level, which tends to be problematic during diagnosis. MicroRNAs are highly conserved non- coding oligonucleotide RNA. Over the last two decades, studies have determined the functional significance of these small RNAs and their impact on cellular development and the interaction between microRNAs and messenger RNAs, which affect numerous molecular pathways and physiological functions. Moreover, many disorders, including breast cancer, are associated with the dysregulation of microRNA. Sparingly, many microRNAs can suppress cancer cell proliferation, apoptosis, angiogenesis, invasion, metastasis, and vice versa. Remarkably, microRNAs can be harvested from patients’ biofluids to predict disease progression that considered a non-invasive method. Nevertheless, MicroRNAs are currently utilized as anti- cancer therapies combined with other drug therapies or even as a single agents’ treatment. Therefore, this review will focus on microRNAs’ role in breast cancer as an indicator of disease progression. In addition, this review summarizes the current knowledge of drug sensitivity and methods in detecting microRNA and their application to improve patient care and identifies the current gaps in this field.

F-FDG PET/CT might discover incidental pituitary lesions. We present the case of a 46-year-old woman with breast cancer metastasis in her pituitary. We analyzed 10,347 FDG PET/CT examinations from a tertiary center, finding 4 cases (0.038%) of pituitary metastatic disease from other cancers. We analyzed the differences between SUVmax in cases of physiological high uptake, primary tumor, and hypophysis metastases from other cancers in our database compared with the literature.

Breast cancer remains the most common malignancy and the leading causality of cancer-associated mortality among women worldwide. With proven efficacy, Oldenlandia diffusa has been extensively applied in breast cancer treatment in Traditional Chinese Medicine (TCM) for thousands of years. However, the bioactive compounds of Oldenlandia diffusa accounting for its anti-breast cancer activity and the underlying biological mechanisms remain to be uncovered. Herein, bioactivity-guided fractionation suggested ursolic acid as the strongest anti-breast cancer compound in Oldenlandia diffusa. Ursolic acid treatment dramatically suppressed the proliferation and promoted mitochondrial-mediated apoptosis in breast cancer cells while brought little cytotoxicities in nonmalignant mammary epithelial cells in vitro. Meanwhile, ursolic acid dramatically impaired both the glycolytic metabolism and mitochondrial respiration function of breast cancer cells. Further investigations demonstrated that ursolic acid may impair the glycolytic metabolism of breast cancer cells by activating Caveolin-1 (Cav-1) signaling, as Cav-1 knockdown could partially abrogate the suppressive effect of ursolic acid on that. Mechanistically, ursolic acid could activate SP1-mediated CAV1 transcription by promoting SP1 expression as well as its binding with CAV1 promoter region. More meaningfully, ursolic acid administration could dramatically suppress the growth and metastasis of breast cancer in both the zebrafish and mouse xenotransplantation models of breast cancer in vivo without any detectable hepatotoxicity, nephrotoxicity or hematotoxicity. This study not only provides preclinical evidence supporting the application of ursolic acid as a promising candidate drug for breast cancer treatment but also sheds novel light on Cav-1 as a druggable target for glycolytic modulation of breast cancer.

Previously, we showed that mice treated with cyclophosphamide (CTX) 4 days before intravenous injection of breast cancer cells had more cancer cells in the lung at 3 h after cancer injection than control counterparts without CTX. At 4 days after its injection, CTX is already excreted from the mice, allowing this pre-treatment design to reveal how CTX may modify the lung environment to indirectly affect cancer cells. In this study, we tested the hypothesis that the increase in cancer cell abundance at 3 h by CTX is due to an increase in the adhesiveness of vascular wall for cancer cells. Our data from protein array analysis and inhibition approach combined with in vitro and in vivo assays support the following two-prong mechanism. (1) CTX increases vascular permeability, resulting in the exposure of the basement membrane (BM). (2) CTX increases the level of matrix metalloproteinase-2 (MMP-2) in mouse serum, which remodels the BM and is functionally important for CTX to increase cancer abundance at this early stage. The combined effect of these two processes is the increased accessibility of critical protein domains in the BM, resulting in higher vascular adhesiveness for cancer cells to adhere. The critical protein domains in the vascular microenvironment are RGD and YISGR domains, whose known binding partners on cancer cells are integrin dimers and laminin receptor, respectively.

Background Metastasis represents the leading cause of death in patients with breast cancer. Traditional Chinese medicine is particularly appreciated for metastatic diseases in Asian countries due to its benefits for survival period prolongation and immune balance modulation. However, the underlying molecular mechanisms remain largely unknown. This study aimed to explore the antimetastatic effect and immunomodulatory function of a clinical formula Aiduqing (ADQ). Methods Naive CD4+ T cells, regulatory T cells (Tregs), and CD8+ T cells were sorted by flow cytometry. Then, breast cancer cells and these immune cells were co-cultured in vitro or co-injected into mice in vivo to simulate their coexistence. Flow cytometry, ELISA, qPCR, double luciferase reporter gene assay, and chromatin immunoprecipitation assay were conducted to investigate the immunomodulatory and antimetastatic mechanisms of ADQ. Results ADQ treatment by oral gavage significantly suppressed 4T1-Luc xenograft growth and lung metastasis in the orthotopic breast cancer mouse model, without noticeable hepatotoxicity, nephrotoxicity, or hematotoxicity. Meanwhile, ADQ remodeled the immunosuppressive tumor microenvironment (TME) by increasing the infiltration of tumor-infiltrating lymphocytes (TILs) and cytotoxic CD8+ T cells, and decreasing the infiltration of Tregs, naive CD4+ T cells, and tumor-associated macrophages (TAMs). Molecular mechanism studies revealed that ADQ remarkably inhibited CXCL1 expression and secretion from TAMs and thus suppressed the chemotaxis and differentiation of naive CD4+ T cells into Tregs, leading to the enhanced cytotoxic effects of CD8+ T cells. Mechanistically, TAM-derived CXCL1 promoted the differentiation of naive CD4+ T cells into Tregs by transcriptionally activating the NF-κB/FOXP3 signaling. Lastly, mouse 4T1-Luc xenograft experiments validated that ADQ formula inhibited breast cancer immune escape and lung metastasis by suppressing the TAM/CXCL1/Treg pathway. Conclusions This study not only provides preclinical evidence supporting the application of ADQ in inhibiting breast cancer metastasis but also sheds novel insights into TAM/CXCL1/NF-κB/FOXP3 signaling as a promising therapeutic target for Treg modulation and breast cancer immunotherapy.

Hanahan and Weinberg introduced the “hallmarks of cancer” and typified essential biological abilities acquired by human cancer. Since then, a growing understanding of hallmark principles associated with breast cancer has assisted knowledge-based therapeutics development; however, despite the rapidly increasing number of targeted therapeutics, enduring disease-free responses for most forms of breast cancer is rare. Invasion and metastasis are the most defining feature of breast cancer malignancy and the leading cause of patient mortality. Hence, we propose a modified hallmarks model adapted to breast cancer, in which invasion and metastasis are shifted to the center of attention, thereby emphasizing it as a potentially superior therapeutic target. Although the scientific community highly appreciates the importance of the invasion and metastasis hallmark, as can be demonstrated by the growing number of publications on breast cancer metastasis, very few clinical trials concentrate on testing anti-metastasis inhibitors and even fewer trials focus on inhibitors for breast cancer metastasis. Here, we discuss the obstacles of applying research on invasion and metastasis therapeutics into the clinic and present current developments that could provide a potential solution to this dilemma.

Previously, we showed that chemotherapy paradoxically exacerbated cancer cell colonization at the secondary site in a manner dependent on Atf3, a stress-inducible gene, in the non-cancer host cells. Here, we present evidence that this phenotype is established at an early stage of colonization within days of cancer cell arrival. Using mouse breast cancer models, we showed that, in the wild-type (WT) lung, cyclophosphamide (CTX) increased the ability of the lung to retain cancer cells in the vascular bed. Although CTX did not change the WT lung to affect cancer cell extravasation or proliferation, it changed the lung macrophage to be pro-cancer, protecting cancer cells from death. This, combined with the initial increase in cell retention, resulted in higher lung colonization in CTX-treated than control-treated mice. In the Atf3 knockout (KO) lung, CTX also increased the ability of lung to retain cancer cells. However, the CTX-treated KO macrophage was highly cytotoxic to cancer cells, resulting in no increase in lung colonization—despite the initial increase in cell retention. In summary, the status of Atf3 dictates the dichotomous activity of macrophage: pro-cancer for CTX-treated WT macrophage but anti-cancer for the KO counterpart. This dichotomy provides a mechanistic explanation for CTX to exacerbate lung colonization in the WT but not Atf3 KO lung.

68Ga-DOTATOC PET/CT is a reliable imaging modality in the diagnosis and therapy planning of symptomatic meningiomas. We present a case of a 74-year-old woman where a supposed SSTR-positive sphenoid wing meningioma turned out to be a breast cancer metastasis. Our case shows that dural metastases from breast cancer might represent a clinical pitfall in 68Ga-DOTATOC PET/CT.

Simple Summary Metastasis remains the greatest cause of fatalities in breast cancer patients world-wide. The process of metastases is highly complex, and the current research efforts in this area are still rather fragmented. The revolution of genomic profiling methods to analyze samples from human and animal models dramatically improved our understanding of breast cancer metastasis. This article summarizes the recent breakthroughs in genomic analyses of breast cancer metastasis and discusses their implications for prognostic and therapeutic applications. Abstract Breast cancer (BC) is one of the most diagnosed cancers worldwide and is the second cause of cancer related death in women. The most frequent cause of BC-related deaths, like many cancers, is metastasis. However, metastasis is a complicated and poorly understood process for which there is a shortage of accurate prognostic indicators and effective treatments. With the rapid and ever-evolving development and application of genomic sequencing technologies, many novel molecules were identified that play previously unappreciated and important roles in the various stages of metastasis. In this review, we summarize current advancements in the functional genomic analysis of BC metastasis and discuss about the potential prognostic and therapeutic implications from the recent genomic findings.

Breast cancer is the most common tumor in women, and the metastasis further increases the malignancy with extremely high mortality. However, there is almost no effective method in the clinic to completely inhibit breast cancer metastasis due to the dynamic multistep process with complex pathways and scattered occurring site. Nowadays, nanomedicines have been evidenced with great potential in treating cancer metastasis. In this review, we summarize the latest research advances of nanomedicines in anti-metastasis treatment. Strategies are categorized according to the metastasis dynamics, including primary tumor, circulating tumor cells, pre-metastatic niches and secondary tumor. In each different stage of metastasis process, nanomedicines are designed specifically with different functions. At the end of the review, we give our perspectives on current limitations and future directions in anti-metastasis therapy. We expect the review provides comprehensive understandings of anti-metastasis therapy for breast cancer, and boosts the clinical translation in the future to improve women's health.

Lobular breast cancer metastasis to bowel is rare, however, when it occurs, the prognosis is poor. Possible benefits of investigation with screening endoscopy for gastrointestinal metastases are discussed in order to optimize prognosis for patients.

Although the contribution of macrophages to metastasis is widely studied in primary tumors, the involvement of macrophages in tumor-draining lymph nodes (LNs) in this process is less clear. We find CD169+ macrophages as the predominant macrophage subtype in naive LNs, which undergo proliferative expansion in response to tumor stimuli. CD169+ LN macrophage depletion, using an anti-CSF-1R antibody or clodronate-loaded liposomes, leads to increased metastatic burden in two mouse breast cancer models. The expansion of CD169+ macrophages is tightly connected to B cell expansion in tumor-draining LNs, and B cell depletion abrogates the effect of CD169+ macrophage absence on metastasis, indicating that the CD169+ macrophage anti-metastatic effects require B cell presence. These results reveal a protective role of CD169+ LN macrophages in breast cancer metastasis and raise caution for the use of drugs aiming at the depletion of tumor-associated macrophages, which might simultaneously deplete macrophages in tumor-draining LNs., Cell Reports, 35 (2), ISSN:2666-3864, ISSN:2211-1247

Cancer cells need to acquire specific molecular traits in order to spread to distant organs. In this issue of Developmental Cell, Marsh et al. show that autophagy restricts the outgrowth of breast cancer metastases in contrast to its impact on primary tumor progression.

Metastasis represents the greatest challenge to treatment of cancer patients. Biomaterial scaffolds that recruit tumor cells to a defined site in vivo are an emerging platform for the diagnosis, treatment, and study of metastasis. Recruitment of immune cells and metastatic tumor cells to a defined location provides a precision health platform to assess current clinical cancer biomarkers in a metastatic setting, and to define the next generation of biomarkers. These platforms represent an opportunity to create a molecular staging of metastasis that could aid in both the early diagnosis and treatment of metastasis.

Background Approximately 10%–15% of patients with breast cancer die of cancer metastasis or recurrence, and early diagnosis of it can improve prognosis. Breast cancer outcomes may be prognosticated on the basis of surface markers of tumor cells and serum tests. However, evaluation of a combination of clinicopathological features may offer a more comprehensive overview for breast cancer prognosis. Materials and methods We evaluated serum human epidermal growth factor receptor 2 (sHER2) as part of a combination of clinicopathological features used to predict breast cancer metastasis using machine learning algorithms, namely random forest, support vector machine, logistic regression, and Bayesian classification algorithms. The sample cohort comprised 302 patients who were diagnosed with and treated for breast cancer and received at least one sHER2 test at Chang Gung Memorial Hospital at Linkou between 2003 and 2016. Results The random-forest-based model was determined to be the optimal model to predict breast cancer metastasis at least 3 months in advance; the correspondingarea under the receiver operating characteristic curve value was 0. 75 (p Conclusion The random-forest-based model presented in this study may be helpful as part of a follow-up intervention decision support system and may lead to early detection of recurrence, early treatment, and more favorable outcomes.

Background Tumor-associated macrophages can promote breast cancer metastasis by secreting cytokines and growth factors. Interleukin (IL)-32θ, a newly identified IL-32 isoform, was previously shown to down-regulate various proinflammatory factors of macrophages. Here, we report the presence of IL-32θ in breast cancer tissues and evaluate its effects on macrophage-regulated breast cancer metastasis. Methods RT-qPCR was used to analyze the mRNA expression of IL-32θ, Chemokine (C-C motif) ligand 18 (CCL18) in breast cancer tissues. In vitro cell-based experiments using IL-32θ-expressing MDA-MB-231 cells were conducted to examine the effects of IL-32θ on metastasis and its molecular signaling. In vivo xenograft, immunohistochemistry, and optical imaging models were generated to support in vitro and clinical findings. Results The clinical data displayed opposite expression patterns of CCL18 and IL-32θ mRNA in macrophage-infiltrated breast tumor tissues compared with those in the other tissues tested. In MDA-MB-231 cells, IL-32θ overexpression attenuated migration, invasion, tumor-promoting factors, and increased epithelial markers levels upon treatment with conditioned media from THP-1-derived macrophages. Additionally, IL-32θ expression in a xenograft model led to a remarkable decrease in tumor size and macrophage-stimulated tumor promotion. This inhibition was mediated through a direct interaction with protein kinase C-δ (PKCδ), subsequently eliminating the downstream factors STAT3 and NF-κB. Blocking CCL18 during co-culture of macrophages and breast cancer cells reduced the levels of breast cancer progression-related factors and PKCδ downstream signaling suggesting CCL18 as the main macrophage-secreted factors triggering the signaling pathway inhibited by IL-32θ. Conclusions Our findings demonstrate a novel role of IL-32θ as an intracellular modulator to suppress macrophage-promoted breast cancer progression by targeting CCL18-dependent signaling. Electronic supplementary material The online version of this article (10.1186/s12964-019-0374-y) contains supplementary material, which is available to authorized users.

Background Differentiating pulmonary metastasis from primary lung cancer can be challenging in patients with breast malignancy. This study aimed to characterize the imaging features of 18 fluorodeoxyglucose-positron emission tomography/computed tomography (18 F-FDG-PET/CT) for distinguishing between these diseases. Methods We enrolled 52 patients who received curative treatment for breast cancer but later presented with suspected solitary pulmonary lesions (SPLs) and subsequently underwent 18 F-FDG-PET/CT to investigate. Results Subsolid lesions, ill-defined borders, lung lesions with negative maximum standardized uptake value, and lesions without 18 F-FDG-PET/CT-diagnosed hilar and/or mediastinal lymph nodes and pleural metastases were more likely to be associated with primary lung cancer. Conclusions CT border, FDG uptake, hilar and/or mediastinal lymph node metastasis, and pleural metastasis are potential markers for diagnosis.

Background As the first member of the metastasis-associated protein (MTA) family, MTA1 and another MTA family member, MTA2, have both been reported to promote breast cancer progression and metastasis. However, the difference and relationship between MTA1 and MTA2 have not been fully elucidated. Methods Transwell assays were used to assess the roles of MTA1 and MTA2 in the metastasis of ZR-75-30 luminal B breast cancer cells in vitro. Immunoblotting and qRT-PCR were used to evaluate the effect of MTA1 overexpression on MTA2. Proteases that cleave MTA2 were predicted using an online web server. The role of neutrophil elastase (NE) in MTA1 overexpression-induced MTA2 downregulation was confirmed by specific inhibitor treatment, knockdown, overexpression and immunocytochemistry, and NE cleavage sites in MTA2 were confirmed by MTA2 truncation and mutation. The effect of MTA1 overexpression on the intrinsic inhibitor of NE, elafin, was detected by qRT-PCR, immunoblotting and treatment with inhibitors. Results MTA1 overexpression inhibited, while MTA2 promoted the metastasis of ZR-75-30 cells in vitro. MTA1 overexpression downregulated MTA2 expression at the protein level rather than the mRNA level. NE was predicted to cleave MTA2 and was responsible for MTA1 overexpression-induced MTA2 degradation. NE was found to cleave MTA2 in the C-terminus at the 486, 497, 542, 583 and 621 sites. MTA1 overexpression activated NE by downregulating elafin in a histone deacetylase- and DNA methyltransferase-dependent manner. Conclusions MTA1 and MTA2 play opposing roles in the metastasis of ZR-75-30 luminal B breast cancer cells in vitro. MTA1 downregulates MTA2 at the protein level by epigenetically repressing the expression of elafin and releasing the inhibition of neutrophil elastase, which cleaves MTA2 in the C-terminus at multiple specific sites. Electronic supplementary material The online version of this article (10.1186/s12964-019-0318-6) contains supplementary material, which is available to authorized users.