Successful treatment of breast metastasis from primary transverse colon cancer:A case report

BACKGROUND The incidence of colon cancer is increasing worldwide.Treatments for colon cancer include surgery and surgery combined with chemotherapy and radiotherapy,but the median survival rate is still poor.Colon cancer most commonly metastasizes to the lymph nodes,lungs,liver,peritoneum,and brain,but breast metastasis is rare.There is no agreement on its treatment.CASE SUMMARY A 23-year-old woman was admitted to our hospital for further treatment with a history of acute abdominal pain,nausea,and vomiting.Her physical examination and computed tomography scan revealed an abdominal tumor.Transverse colectomy was successfully performed.Histopathological examination revealed that the tumor was a mucosecretory adenocarcinoma with signet ring cells.The patient inadvertently found a mass in the outer upper quadrant of the right breast after four cycles of XELOX chemotherapy[oxaliplatin 130 mg/m^(2),d1,intravenous(iv)drip for 2 h;capecitabine 1000 mg/m^(2),po,bid,d1–d14].After discussion with the patient,we performed a lumpectomy and frozen biopsy.The latter revealed that the breast tumor was intestinal metastasis.Genetic testing showed wild-type RAS and BRAF.So we replaced the original chemotherapy with FOLFIRI[irinotecan 180 mg/m^(2),d1,iv drip for 3–90 min;leucovorin 400 mg/m^(2),d1,iv drip for 2 h;5-fluorouracil(5-FU)400 mg/m^(2),d1 and 5-FU 1200 mg/(m^(2)d)×2 d,continuous iv drip for 46–48 h]+cetuximab(500 mg/m^(2),d1,iv drip for 2 h).Serum levels of tumor markers returned to normal after several treatment cycles,and there was no evidence of tumor recurrence or metastasis.CONCLUSION Breast metastasis from colon cancer is rare.Radical breast surgery should be avoided unless needed for palliation.Chemotherapy combined with targeted therapy should be the first choice.

Nasopharyngeal carcinoma with synchronous breast metastasis:A case report

BACKGROUND Recent reports have described cases of metachronous breast metastasis in patients with nasopharyngeal carcinoma.However,no similar cases of synchronous breast metastasis have been reported,and evidence that can be used to support the clinical diagnosis of stage IV nasopharyngeal carcinoma in patients with concurrent breast metastasis remains lacking.Therefore,additional evidence is required to elucidate the clinical characteristics of this condition and aid in the development of optimal management strategies.CASE SUMMARY We report the case of a 46-year-old woman who visited our hospital with a right breast mass as the first symptom.The first pathological biopsy report suggested triple-negative breast invasive carcinoma.Subsequent imaging revealed a nasopharyngeal mass.Further puncture biopsy of the nasopharyngeal mass,molecular pathological Epstein–Barr virus in situ hybridization,and immunohistochemistry confirmed the diagnosis of nasopharyngeal carcinoma with breast metastasis.The patient did not undergo a mastectomy and achieved complete remission after chemotherapy and radiotherapy.She continued to receive oral chemotherapy as maintenance therapy and experienced no recurrence or metastasis during the 6-month follow-up period.CONCLUSION This case report suggests that breast specialists should carefully rule out secondary breast cancers when diagnosing and treating breast masses.Furthermore,clinicians should aim to identify the pathological type of the tumor to obtain the most accurate diagnosis and prevent excessive diagnosis and treatment.

Gastric signet-ring adenocarcinoma presenting with breast metastasis

Breast metastases from gastric cancer are extremely rare. A case report of a 37-year-old female with breast inflammatory invasion and ascites is described. Breast biopsy revealed carcinomatous invasion of the lymphatics from adenocarcinoma cells with signet-ring features. Estrogen （ER） and progesterone receptors （PR） and c-erb-B2 were negative. Upper gastrointestinal endoscopy revealed a prepyloric ulcerative mass. Histopathologic examination of the lesion showed infiltration from a highgrade adenocarcinoma, identical with that of the breast. Immunostaining was positive for cytokeratins CK-7 and CK-20 and CEA and negative for ER and PR. Ascitic fluid cytology was positive for adenocarcinoma cells. Mammography was not diagnostic. Abdominal CT scanning revealed large ovarian masses suggestive of metastases （Krukenberg＇s tumor）. A cisplatin-based regimen was given but no objective response was observed. The patient died six months after initial diagnosis. A review of the literature is performed.

Case Report:Breast metastasis from small cell lung carcinoma

Breast metastases from extramammary neoplasms are very rare. We presented a 66 year-old female with metastasis of small cell lung carcinoma to the breast. She presented with consolidation over the left upper lobe of her lung undetermined after endobronchial or video-assisted thoracoscopic surgery (VATS) biopsy,and this was treated effectively after antibiotic therapy at initial stage. The left breast lumps were noted 4 months later,and she underwent a modified radical mastectomy under the im-pression of primary breast carcinoma. However,the subsequent chest imaging revealed re-growing mass over the left mediastinum and hilum,and cells with the same morphological and staining features were found from specimens of transbronchial brushing and biopsy. An accurate diagnosis to distinguish a primary breast carcinoma from metastatic one is very important because the therapeutic planning and the outcome between them are different.

Subcutaneous and breast metastasis from asymptomatic gallbladder carcinoma

BACKGROUND:Though gallbladder carcinoma is asso- ciated with early lymphatic and hematogenous spread, the only common extra-abdominal site of metastasis is lung.Gallbladder carcinoma metastasizing to breast and subcutaneous tissue is not known. METHOD:This report describes an interesting and unusual case of asymptomatic gallbladder carcinoma presenting with subcutaneous and breast metastasis. RESULTS:A 42-year-old woman presented with multiple subcutaneous nodules over the abdominal wall,anterior chest wall,back and in bilateral breasts.Fine needle aspiration cytology(FNAC)of these nodules revealed metastatic adenocarcinoma.The patient was investigated for a primary neoplasm.An ultrasound of the abdomen followed by a contrast-enhanced CT scan showed a growth in gallbladder,infiltrating the liver with multiple hepatic metastases.CT-guided FNAC from the growth in the gallbladder revealed adenocarcinoma.She was diagnosed as a case of metastatic adenocarcinoma of the gallbladder and palliative combination chemotherapy with gemcitabine and carboplatin was given.But she developed jaundice and deteriorated dramatically in a short span of time.No specific therapy could be started and she was given supportive treatment.She died within three weeks of diagnosis due to hepatic encephalopathy. CONCLUSIONS:This report highlights an unusual metastasis of gallbladder carcinoma to the breast and subcutaneous tissue presenting as multiple lesions,which has never been reported in the English literature.These were unknown sites of metastasis for carcinoma of the gallbladder.Moreover,bilateral multiple metastatic lesions to breast are also very rare.

Breast metastasis from lung cancer：a report of two cases and literature review

Breast metastasis from extra-mammary malignancy is rare. An incidence of 0.4% to 1.3% has been reported in literature. The primary malignancies that most commonly metastasize to the breast are leukemia, lymphoma, and malignant melanoma. In this report, two cases of pulmonary metastasis to the breast were presented. A 40-year-old female manifested a right breast mass of 2-month duration. After physical examination was performed, a poorly defined mass was noted in the upper outer quadrant of the right breast. Another 49-year-old female manifested right breast mass of 5-day duration. A poorly defined mass was noted in the lower inner quadrant of the right breast. Mammography results also revealed breast cancer. The patients underwent local excision. After histological and immunohistochemical analyses were conducted, a primary lung carcinoma that metastasized to the breast was diagnosed. An accurate differentiation of metastasis to the breast from primary breast cancer is very important because the treatment and prognosis of the two differ significantly.

Inetetamab combined with pyrotinib and chemotherapy in the treatment of breast cancer brain metastasis: A case report

BACKGROUND Breast cancer brain metastasis(BCBM)is an advanced breast disease that is difficult to treat and is associated with a high risk of death.Patient prognosis is usually poor,with reduced quality of life.In this context,we report the case of a patient with HER-2-positive BCBM treated with a macromolecular mAb(ine-tetamab)combined with a small molecule tyrosine kinase inhibitor(TKI).CASE SUMMARY The patient was a 58-year-old woman with a 12-year history of type 2 diabetes.She was compliant with regular insulin treatment and had good blood glucose control.The patient was diagnosed with invasive carcinoma of the right breast(T3N1M0 stage IIIa,HER2-positive type)through aspiration biopsy of the ipsilateral breast due to the discovery of a breast tumor in February 2019.Immunohistochemistry showed ER(-),PR(-),HER-2(3+),and Ki-67(55-60%+).Preoperative neoadjuvant chemotherapy,i.e.,the AC-TH regimen(epirubicin,cyclophosphamide,docetaxel-paclitaxel,and trastuzumab),was administered for 8 cycles.She underwent modified radical mastectomy of the right breast in November 2019 and received tocilizumab targeted therapy for 1 year.Brain metastasis was found 9 mo after surgery.She underwent brain metastasectomy in August 2020.Immunohistochemistry showed ER(-)and PR.(-),HER-2(3+),and Ki-67(10-20%+).In November 2020,the patient experienced headache symptoms.After an examination,tumor recurrence in the original surgical region of the brain was observed,and the patient was treated with inetetamab,pyrotinib,and capecitabine.Whole-brain radiotherapy was recommended.The patient and her family refused radiotherapy for personal reasons.In September 2021,a routine examination revealed that the brain tumor was considerably larger.The original systemic treatment was continued and combined with intensity-modulated radiation therapy for brain metastases,followed by regular hospitalization and routine examinations.The patient’s condition is generally stable,and she has a relatively high quality of life.This case report demonstrates that in patients with BCBM and resistance to trastuzumab,inetetamab combined with pyrotinib and chemotherapy can prolong survival.CONCLUSION Inetetamab combined with small molecule TKI drugs,chemotherapy and radiation may be an effective regimen for maintaining stable disease in patients with BCBM.

Apigenin is an anoikis sensitizer with strong anti-metastatic properties in experimental breast cancer

Loss of susceptibility to anoikis signals is a crucial step in metastasis.Anoikis resistance therefore represents a promising adjuvant therapeutic target for cancer management.In this study,we have conducted a rationalized screening to search for novel leading anoikis sensitizer from daily foods.Among 19 tested dietary phytochemicals,the best results were obtained with apigenin,a natural component of celery.Phenotypically,apigenin sensitized breast cancer cells to anoikis,lowered the number of circulating tumor cells,and protected against breast cancer metastasis to lung in mice.Mechanistically,we demonstrated that the thromboxane A_(2)(TXA_(2))-TXA_(2)receptor(TP)axis has a critical role in acquired anoikis resistance by activating PI3K-Akt signaling pathway.Blockage of TXA_(2)signaling up-regulated p53 as well as its target gene p21,caused a G1 phase arrest,and finally led to apoptosis in breast cancer cells.TXA_(2)level was positively correlated with breast cancer cell anoikis rate,and apigenin significantly inhibited TXA_(2)biosynthesis in vitro and in vivo.Collectively,we identified apigenin as a potent anoikis sensitizer with anti-metastatic properties in a mouse model of breast cancer,and these findings might provide a rationale for introducing apigenin supplementation to breast cancer patients.

Dual ligand-targeted Pluronic P123 polymeric micelles enhance the therapeutic effect of breast cancer with bone metastases

Bone metastasis secondary to breast cancer negatively impacts patient quality of life and survival.The treatment of bone metastases is challenging since many anticancer drugs are not effectively delivered to the bone to exert a therapeutic effect.To improve the treatment efficacy,we developed Pluronic P123(P123)-based polymeric micelles dually decorated with alendronate(ALN)and cancer-specific phage protein DMPGTVLP(DP-8)for targeted drug delivery to breast cancer bone metastases.Doxorubicin(DOX)was selected as the anticancer drug and was encapsulated into the hydrophobic core of the micelles with a high drug loading capacity(3.44%).The DOX-loaded polymeric micelles were spherical,123 nm in diameter on average,and exhibited a narrow size distribution.The in vitro experiments demonstrated that a pH decrease from 7.4 to 5.0 markedly accelerated DOX release.The micelles were well internalized by cultured breast cancer cells and the cell death rate of micelle-treated breast cancer cells was increased compared to that of free DOX-treated cells.Rapid binding of the micelles to hydroxyapatite(HA)microparticles indicated their high affinity for bone.P123-ALN/DP-8@DOX inhibited tumor growth and reduced bone resorption in a 3D cancer bone metastasis model.In vivo experiments using a breast cancer bone metastasis nude model demonstrated increased accumulation of the micelles in the tumor region and considerable antitumor activity with no organ-specific histological damage and minimal systemic toxicity.In conclusion,our study provided strong evidence that these pH-sensitive dual ligand-targeted polymeric micelles may be a successful treatment strategy for breast cancer bone metastasis.

Simultaneous breast and ovarian metastasis from gallbladder carcinoma

BACKGROUND:Gallbladder carcinoma is a common malignancy in the Indian subcontinent.It commonly metastasizes through lymphatics,direct invasion,and hematogenous spread.A common extra-abdominal site of metastasis is the lungs.Simultaneous metastasis to breast and ovary is extremely rare.METHOD:This report describes an unusual case of carcinoma gallbladder metastasizing to the breast and ovary at the same time.RESULTS:A 45-year-old woman came to us with complaints of flatulent dyspepsia associated with weight loss and anorexia.Ultrasound of the abdomen revealed hepatomegaly with thick-walled gallbladder with multiple stones and a mass at the fundus,but normal uterus and ovary.Contrast-enhanced computer tomography of the abdomen showed a gallbladder mass infiltrating the liver parenchyma.The patient underwent radical cholecystectomy.Histopathological examination revealed a poorly-differentiated adenocarcinoma with margins free from tumor infiltration.One month after surgery she developed a breast lump.Ultrasound of the abdomen for metastatic workup revealed an ovary mass.Simple mastectomy and salphingo-opherectomy were performed,and histopathological examination revealed a metastatic adenocarcinoma.The patient is now on chemotherapy with gemcitabin.CONCLUSION:This is an unusual case of carcinoma of the gallbladder with metastasis to the breast and ovary,which has not been documented before.

Isolated breast metastasis mimicking as second primary cancer-a case report

Primary carcinoma of breast is common but breast is a rare site of metastasis and metastases from extramammary sites are even rarer.Metastasis to breast from rectal carcinoma is very unusual and till now 19 cases of breast secondaries from colorectal carcinoma have been reported in literature which include 14 cases where the primary site was colon and remaining 5 were from the rectum.Here the authors report a case of adenocarcinoma anorectum who had completed treatment and after 4 months developed a lump in her left breast which was metastatic.Metastatic lesions of breast are usually part of a widely disseminated disease but this case presented as a solitary breast metastasis which mimicked as second primary cancer of the breast.

Ononin inhibits triple-negative breast cancer lung metastasis by targeting the EGFR-mediated PI3K/Akt/mTOR pathway

The spreading of cancer cells from the primary tumor site to other parts of the body,known as metastasis,is the leading cause of cancer recurrence and mortality in patients with triple-negative breast cancer(TNBC).Overexpression of epidermal growth factor receptor(EGFR)is observed in approximately 70%of TNBC patients.EGFR is crucial for promoting tumor metastasis and associated with poor prognosis.Therefore,it is vital to identify effective therapeutic strategies targeting EGFR inhibition.Ononin,an isoflavonoid found in various plants,such as clover and soybeans,has been shown to have anticancer properties in several cancers.In the present study,we aimed to investigate the effects of ononin on TNBC lung metastasis and the associated molecular pathways.We used various assays,including cell viability,colony formation,Transwell,wound healing,ELISA,Western blotting,and staining techniques,to achieve this objective.The results demonstrated that ononin effectively suppressed cellular proliferation and induced apoptosis,as evidenced by the cell viability assay,colony formation assay,and expression of apoptosis markers,and reduced the metastatic capabilities of TNBC cells.These effects were achieved through the direct suppression of cell adhesion,invasiveness and motility.Furthermore,in TNBC xenograft lung metastatic models,ononin treatment significantly reduced tumor growth and lung metastasis.Additionally,ononin reversed the epithelial-mesenchymal transition(EMT)by downregulating the expression of EMT markers and matrix metalloproteinases,as confirmed by Western blot analysis.Furthermore,ononin treatment reduced EGFR phosphorylation and suppressed the PI3K,Akt,and m TOR signaling pathways,which was further confirmed using EGFR agonists or inhibitors.Importantly,ononin treatment did not exert any toxic effects on liver or kidney function.In conclusion,our findings suggest that ononin is a safe and potentially therapeutic treatment for TNBC metastasis that targets the EGFRmediated PI3K/Akt/m TOR pathway.Further studies are warranted to validate its efficacy and explore its potential clinical applications.

A nanoagent for concurrent therapy of breast cancer bone metastasis and cancer-induced bone pain through SLC7A11 interruption and photodynamic therapy

Bone metastasis,a life-threatening complication of advanced breast cancer,is often accompanied by debilitating pain(cancer-induced bone pain,CIBP)that severely impairs life quality and survival.The concurrent treatment of bone metastases and CIBP remains a clinical challenge because the therapeutic options are limited.In this study,we construct a near-infrared light-activated nano-therapeutic system to meet this conundrum.In detail,sorafenib(SRF)and photosensitizer(chlorin e6,Ce6)are encapsulated into mesoporous hydroxyapatite nanoparticles(HANPs),which are further functionalized with hyaluronic acid(HA)to obtain HA-SRF/Ce6@HANPs system.The designed nanoplatform destroys tumor cells in vitro and in vivo via the synergism of SRF(interrupting the exchange of cystine/glutamate by inhibiting SLC7A11)and photodynamic therapy(PDT,inducing reactive oxygen species generation).The decrease in tumor burden and reduction of extracellular glutamate significantly attenuate CIBP in mice model with developing bone cancer.Moreover,the combination of HA-SRF/Ce6@HANPs and PDT inhibit osteoclasts activation,promote osteoblast differentiation and accelerate bone repair.Overall,the nanoagent with good biocompatibility may provide an effective therapy method for the concurrent treatment of breast cancer bone metastasis and CIBP.

Enterolactone modulates the ERK/NF-κB/Snail signaling pathway in triple-negative breast cancer cell line MDA-MB-231 to revert the TGF-β-induced epithelial–mesenchymal transition

Objective:Triple-negative breast cancer(TNBC)is highly metastatic,and there is an urgent unmet need to develop novel therapeutic strategies leading to the new drug discoveries against metastasis.The transforming growth factor-β(TGF-β)is known to promote the invasive and migratory potential of breast cancer cells through induction of epithelial–mesenchymal transition(EMT)via the ERK/NF-κB/Snail signaling pathway,leading to breast cancer metastasis.Targeting this pathway to revert the EMT would be an attractive,novel therapeutic strategy to halt breast cancer metastasis.Methods:Effects of enterolactone(EL)on the cell cycle and apoptosis were investigated using flow cytometry and a cleaved caspase-3 enzyme-linked immunosorbent assay(ELISA),respectively.Effects of TGF-βinduction and EL treatment on the functional malignancy of MDA-MB-231 breast cancer cells were investigated using migration and chemo-invasion assays.The effects of EL on EMT markers and the ERK/NF-κB/Snail signaling pathway after TGF-βinduction were studied using confocal microscopy,quantitative reverse transcription polymerase chain reaction(q RT-PCR),Western blot,and flow cytometry.Results:Herein,we report that EL exhibits a significant antimetastatic effect on MDA-MB-231 cells by almost reverting the TGF-β-induced EMT in vitro.EL downregulates the mesenchymal markers N-cadherin and vimentin,and upregulates the epithelial markers E-cadherin and occludin.It represses actin stress fiber formation via inhibition of mitogen-activated protein kinase p-38(MAPK-p38)and cluster of differentiation 44(CD44).EL also suppresses ERK-1/2,NF-κB,and Snail at the m RNA and protein levels.Conclusions:Briefly,EL was found to inhibit TGF-β-induced EMT by blocking the ERK/NF-κB/Snail signaling pathway,which is a promising target for breast cancer metastasis therapy.

Adipocyte-derived SFRP5 inhibits breast cancer cells migration and invasion through Wnt and epithelial-mesenchymal transition signaling pathways

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 epithelialmesenchymal 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.

Rectal Cancer Metastasizing to Breast: A Case Report and Review of Literature

Objectives: To report rare metastasis in breast from rectal cancer. Case Report: A 47-year-old married lady who presented with rectal bleeding for six weeks and diagnosed as a case of adenocarcinoma with no metastasis underwent neoadjuvent radiotherapy and chemotherapy and then abdominoperineal resection on follow-up found to have left breast mass and skin lesion in upper abdominal wall. Mammogram showed BIRADS-5. Tru cut biopsy showed mucinous/signet ring adenocarcinoma and she underwent lumpectomy and sentinel lymph node biopsy and excision of skin lesion. Histopathology of breast lump and skin lesion came as mucinous adeno-carcinoma of colonic origin, but all axillary lymph nodes were negative for malignancy. Conclusion: Metastatic breast lump is rare entity and every effort to be put to diagnose it using modern diagnostic tools.

Predicting survival and prognosis of postoperative breast cancer brain metastasis:a population-based retrospective analysis

Background:Breast cancer is one of the most common cancer in women and a proportion of patients experiences brain metastases with poor prognosis.The study aimed to construct a novel predictive clinical model to evaluate the overall survival(OS)of patients with postoperative brain metastasis of breast cancer(BCBM)and validate its effectiveness.Methods:From 2010 to 2020,a total of 310 female patients with BCBM were diagnosed in The Affiliated Cancer Hospital of Xinjiang Medical University,and they were randomly assigned to the training cohort and the validation cohort.Data of another 173 BCBM patients were collected from the Surveillance,Epidemiology,and End Results Program(SEER)database as an external validation cohort.In the training cohort,the least absolute shrinkage and selection operator(LASSO)Cox regression model was used to determine the fundamental clinical predictive indicators and the nomogram was constructed to predict OS.The model capability was assessed using receiver operating characteristic,C-index,and calibration curves.Kaplan-Meier survival analysis was performed to evaluate clinical effectiveness of the risk stratification system in the model.The accuracy and prediction capability of the model were verified using the validation and SEER cohorts.Results:LASSO Cox regression analysis revealed that lymph node metastasis,molecular subtype,tumor size,chemotherapy,radiotherapy,and lung metastasis were statistically significantly correlated with BCBM.The C-indexes of the survival nomogram in the training,validation,and SEER cohorts were 0.714,0.710,and 0.670,respectively,which showed good prediction capability.The calibration curves demonstrated that the nomogram had great forecast precision,and a dynamic diagram was drawn to increase the maneuverability of the results.The Risk Stratification System showed that the OS of lowrisk patients was considerably better than that of high-risk patients(P<0.001).Conclusion:The nomogram prediction model constructed in this study has a good predictive value,which can effectively evaluate the survival rate of patients with postoperative BCBM.

HBXIP blocks myosin-ⅡA assembly by phosphorylating and interacting with NMHC-ⅡA in breast cancer metastasis

Tumor metastasis depends on the dynamic balance of the actomyosin cytoskeleton.As a key component of actomyosin filaments,non-muscle myosin-ⅡA disassembly contributes to tumor cell spreading and migration.However,its regulatory mechanism in tumor migration and invasion is poorly understood.Here,we found that oncoprotein hepatitis B X-interacting protein(HBXIP) blocked the myosin-ⅡA assemble state promoting breast cancer cell migration.Mechanistically,mass spectrometry analysis,co-immunoprecipitation assay and GST-pull down assay proved that HBXIP directly interacted with the assembly-competent domain(ACD) of non-muscle heavy chain myosin-ⅡA(NMHC-ⅡA).The interaction was enhanced by NMHC-ⅡA S1916 phosphorylation via HBXIP-recruited protein kinase PKCβⅡ.Moreover,HBXIP induced the transcription of PRKCB,encoding PKCβⅡ,by coactivating Sp1,and triggered PKCβⅡ kinase activity.Interestingly,RNA sequencing and mouse metastasis model indicated that the anti-hyperlipidemic drug bezafibrate(BZF) suppressed breast cancer metastasis via inhibiting PKCβⅡ-mediated NMHC-ⅡA phosphorylation in vitro and in vivo.We reveal a novel mechanism by which HBXIP promotes myosin-ⅡA disassembly via interacting and phosphorylating NMHC-ⅡA,and BZF can serve as an effective anti-metastatic drug in breast cancer.

CSF2 upregulates CXCL3 expression in adipocytes to promote metastasis of breast cancer via the FAK signaling pathway

Recent studies have demonstrated that cancer-associated adipocytes (CAAs) in the tumor microenvironment are involved in the malignant progression of breast cancer. However, the underlying mechanism of CAA formation and its effects on the development of breast cancer are still unknown. Here, we show that CSF2 is highly expressed in both CAAs and breast cancer cells. CSF2 promotes inflammatory phenotypic changes of adipocytes through the Stat3 signaling pathway, leading to the secretion of multiple cytokines and proteases, particularly C–X–C motif chemokine ligand 3 (CXCL3). Adipocyte-derived CXCL3 binds to its specific receptor CXCR2 on breast cancer cells and activates the FAK pathway, enhancing the mesenchymal phenotype, migration, and invasion of breast cancer cells. In addition, a combination treatment targeting CSF2 and CXCR2 shows a synergistic inhibitory effect on adipocyte-induced lung metastasis of mouse 4T1 cells in vivo. These findings elucidate a novel mechanism of breast cancer metastasis and provide a potential therapeutic strategy for breast cancer metastasis.