Metastatic Breast Research Articles

GOBLET platform study: Preliminary safety and tumor response results for the relapsed anal carcinoma cohort in patients treated with pelareorep and atezolizumab.

6 Background: Patients with relapsed unresectable squamous cell carcinoma of the anal canal (SCCA) have limited treatment options after failure of standard first-line therapy. While checkpoint inhibitor monotherapy is possible, response rates are low (10-24%). Therapies that induce an inflammatory tumor microenvironment may improve the susceptibility of SCCA to immunotherapy. Pelareorep (pela) is a non-genetically modified, intravenously administered reovirus that stimulates the expansion of tumor-infiltrating lymphocyte (TIL) clones and simultaneously makes tumors visible to the immune system by upregulating interferon-induced gene expression. Pela-based combination therapies have demonstrated activity in metastatic breast and pancreatic cancer. In the GOBLET platform study, the efficacy of pela plus atezolizumab (atezo) in SCCA is being evaluated. Methods: GOBLET is a phase 1/2, open-label, non-randomized, Simon two-stage platform study in patients with advanced or metastatic GI cancers. SCCA patients in the trial are treated with pela plus atezo. Ten evaluable patients will be enrolled in Stage 1 and an additional 18 evaluable patients will be enrolled in Stage 2 if the prespecified Stage 1 success criterion is met (≥2 responses). The coprimary endpoints are tolerability of the treatment regimen and objective response rate (based on RECIST v1.1). Safety data are reviewed in an ongoing manner by an independent Data Safety Monitoring Board (DSMB). In addition, tumor and blood samples are being collected to assess TIL clonal expansion and other biomarkers. Results: Twelve patients are currently evaluable for tumor response in the SCCA cohort. Four out of 12 patients have achieved an objective response to therapy including 1 prolonged complete response (>15 months) and 3 partial responses- resulting in an ORR of 33.3%. Final ORR, progression-free survival, and overall survival results are pending. The DSMB has identified no safety signals and has recommended that enrollment continues without modification. TIL clonal expansion in the blood has been observed at treatment cycle 4 in all 3 responding patients for whom data are available. Conclusions: Twelve patients are currently evaluable for tumor response in the SCCA cohort. Four out of 12 patients have achieved an objective response to therapy including 1 prolonged complete response (>15 months) and 3 partial responses resulting in an ORR of 33.3%. Final ORR, progression-free survival, and overall survival results are pending. The DSMB has identified no safety signals and has recommended that enrollment continues without modification. TIL clonal expansion in the blood has been observed at treatment cycle 4 in all 3 responding patients for whom data are available. Clinical trial information: 2020-003996-16.

Targeting FOXM1 condensates reduces breast tumour growth and metastasis.

Identifying phase-separated structures remains challenging, and effective intervention methods are currently lacking1. Here we screened for phase-separated proteins in breast tumour cells and identified forkhead (FKH) box protein M1 (FOXM1) as the most prominent candidate. Oncogenic FOXM1 underwent liquid-liquid phase separation (LLPS) with FKH consensus DNA element, and compartmentalized the transcription apparatus in the nucleus, thereby sustaining chromatin accessibility and super-enhancer landscapes crucial for tumour metastatic outgrowth. Screening an epigenetics compound library identified AMPK agonists as suppressors of FOXM1 condensation. AMPK phosphorylated FOXM1 in the intrinsically disordered region (IDR), perturbing condensates, reducing oncogenic transcription, accumulating double-stranded DNA to stimulate innate immune responses, and endowing discrete FOXM1 with the ability to activate immunogenicity-related gene expressions. By developing a genetic code-expansion orthogonal system, we demonstrated that a phosphoryl moiety at a specific IDR1 site causes electrostatic repulsion, thereby abolishing FOXM1 LLPS and aggregation. A peptide targeting IDR1 and carrying the AMPK-phosphorylated residue was designed to disrupt FOXM1 LLPS and was shown to inhibit tumour malignancy, rescue tumour immunogenicity and improve tumour immunotherapy. Together, these findings provide novel and in-depth insights on function and mechanism of FOXM1 and develop methodologies that hold promising implications in clinics.

Uncommon Breast Metastasis From Rectal Carcinoma Clearly Revealed on 68Ga-FAPI-04 PET/CT

Abstract Breast metastasis from rectal carcinoma is very rare. We report a case of imaging findings of breast metastasis in a 31-year-old woman who underwent laparoscopic radical tumor resection 8 months ago. 68Ga-FAPI-04 PET/CT and 18F-FDG PET/CT showed 4 small breast nodules with intense 68Ga-FAPI uptake (SUVmax, 9.22) but slight 18F-FDG uptake (SUVmax, 1.95). Needle biopsy supported a diagnosis of metastasis from rectal adenocarcinoma.

Ovarian cancer with breast metastasis: a rare case report

Introduction: Ovarian cancer with breast metastasis is an exceedingly rare entity. We hereby reported a case of ovarian cancer presenting with synchronous breast metastasis. Case presentation: We report a case of a 39-year-old patient who was diagnosed with FIGO stage IV ovarian cancer, with pleural effusion and a suspected lesion in the breast. Biopsies of the breast lesion showed invasive carcinoma, immunohistochemistry stains of the breast biopsy specimen were positive for PAX-8, CA-125 markers, and negative for P53, SMA, Her2/neu, Mammaglobin. Immunohistochemistry results combined with the diagnosis of ovarian cancer helped confirm the ovarian origin of breast tumor. Discussion: Ovarian cancer presenting with breast cancer metastasis concurrently is rare. The differential diagnosis between primary breast cancer and breast metastasis from ovarian cancer is challenging and immunohistochemistry results play a crucial role in establishing a definitive diagnosis in such cases. Conclusion: Oncologist and pathologist should be able to identify this rare clinical scenario promptly for early diagnosis and treatment which relies on thorough examination, imaging and immunohistochemical studies. Nevertheless, owing to the extensive spread of the disease, the prognosis for this rare clinical scenario is generally poor.

RURAL HEALTH AND FAMILY CAREGIVING: IDENTIFYING CHARACTERISTICS AND ADDRESSING NEEDS ACROSS POPULATIONS

Abstract The rural population in the U.S. is growing and aging faster, and they have more comorbidities, than the overall aging population. Despite the greater need for resources and supports, rural residents may experience the most barriers to formal services (e.g., hospital, hospice/palliative care, nursing home care) and may lack available family caregivers. Unfortunately, there is a dearth of population-based research comparing the characteristics and needs of older adults living and dying in rural vs. urban areas, particularly related to availability of family. This symposium includes 4 presentations focused on rural health and family caregiving and identifying the characteristics and addressing needs across populations. The first presentation uses a retrospective population cohort design with cancer registry and state-wide claims data to examine urban/rural differences in palliative care-related service claims among older adult cancer patients diagnosed with metastatic breast, lung, colorectal, head and neck, bladder, and melanoma cancers. The next two presentations use data from the Utah Caregiving Population Study (Utah C-PopS) to examine how family size and characteristics impact EOL care utilization for urban vs. rural NH residents and for persons with dementia. The last presentation describes a program evaluation of an interagency collaboration to support caregivers in rural communities. Together, these presentations shed light on the diverse characteristics, gaps in care, and novel strategies to address the needs of rural populations to better inform rural health practice and policy considerations.

Novel benzoylurea derivative decreases TRPM7 channel function and inhibits cancer cells migration

ABSTRACT The transient receptor potential melastatin 7 channel (TRPM7) is a nonselective cation channel highly expressed in some human cancer tissues. TRPM7 is involved in the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of cancer cells. Modulation of TRPM7 could be a promising therapeutic strategy for treating cancer; however, efficient and selective pharmacological TRPM7 modulators are lacking. In this study we investigated N- [4- (4, 6-dimethyl- 2-pyrimidinyloxy) − 3- methylphenyl] -N’ - [2 -(dimethylamino)] benzoylurea (SUD), a newly synthesized benzoylurea derivative, for its effects on cancer cell migration and EMT and on functional expression of TRPM7. Our previous studies showed that SUD induces cell cycle arrest and apoptosis of MCF-7 and BGC-823 cells (human breast cancer and gastric cancer cell lines, respectively). Here, we show that SUD significantly decreased the migration of both types of cancer cells. Moreover, SUD decreased vimentin expression and increased E-cadherin expression in both cell types, indicating that EMT is also decreased by SUD. Importantly, SUD potentially reduced the TRPM7-like current in a concentration-dependent manner and decreased TRPM7 expression through the PI3K/Akt signaling pathway. Finally, molecular docking simulations were used to investigate potential SUD binding sites on TRPM7. In summary, our research demonstrated that SUD is an effective TRPM7 inhibitor and a potential agent to suppress the metastasis of breast and gastric cancer by inhibiting TRPM7 expression and function.

Evaluation of therapy support through a standardized nursing consultation for patients undergoing oral tumor therapy in gynecological oncology within the prospective CAMPA initiative.

The increase of oral tumor therapies (OTT) poses new challenges in patient care. Within CAMPA (Care improvement for advanced or metastatic breast and ovarian cancer patients treated with PARP-inhibitors), additional nursing support for patients treated with PARP-inhibitors was developed. Additional nursing support (1 year) was evaluated in breast and gynecooncological cancer patients at an academic and a non-academic outreach center. From 02/22 to 02/24, quality of life, contacts, adherence, documentation of drug intake, hospitalization, and adverse events were evaluated, using CANKADO-ePRO and validated questionnaires reviewed by the Ethics Committee of Medical Faculty, LMU Munich. Satisfaction with care was recorded from 03/23 to 02/24. Supporting materials and interprofessional checklists were explored. The collective (n=50) included 41 patients with ovarian, 4 with fallopian tube and 5 with breast cancer. Adherence measured by continuous documentation of medication intake was high among patients (78.0%). Quality of life improved from 68.6% to 81.4%, strongly correlating with decreasing numbers of side effects (p=0.003) (Spearman |ρ|=0.93). Satisfaction with care was very high (4.97 out of 5 points). 94.6% agreed that nursing consultation was essential for therapy safety compared to the doctor's consultation alone (p<0.05). The reduction in time and care effort was significant (p<0.05), having its maximum within the first three months. Standardized nursing consultation was highly appreciated with an important contribution to adherence and improvement in quality of life. Delegation of therapy management to nurses reduces time effort and increases their responsibility, improving interprofessional care at academic and non-academic institutions. Clinical Trials Registry, LMU university hospital, Germany, Healthcare research project, number: 21-0848.

Bone metastasis in endocrine-related cancer: unravelling invasion and destruction.

Bone is a common and debilitating site for metastatic cancer cell expansion. Skeletal metastasis is a multistage process, with primary stages of circulating tumour cells, progressing to a dormant state in vasculature and bone marrow niches, followed by tumorigenic reactivation, proliferation, and finally bone destruction. The frequency of bone metastasis is reconciled in Paget's "seed and soil" hypothesis, where a conducive microenvironment (bone niche) is essential for cancer cell colonisation. Cancer cells can mimic bone cells (osteomimicry) and interact with the bone marrow's vascular architecture, utilising pathways akin to hematopoietic stem cell expansion. Current research suggests that each phase of bone metastasis is associated with specific gene expression and protein abundance patterns. For example, E-selectin, CXCR-4, and CXCL-12 are crucial for cancer cell homing, dormancy, and colonisation of bone tissue. In contrast, different primary cancers appear to have unique staging profiles. In prostate cancer, dormancy is modulated by the CXCR-4/CXCL-12, ANXA2/CXCL12, and GAS6 pathways, while in breast cancer, dormancy involves ERK1/2, p38, MSK1, LIF, BMP-7, TGF-β1/2, and bone resorption factors. Conversely, osteoblastic metastasis in both breast and prostate cancers is characterised by ET-1, Dkk1 suppression, and the release of IL-6, MCP-1, VEGF, FGF, and IGF, while osteolytic metastasis primarily depends on PTHrP, RANKL, OPG, TGF-β, IGF, TNF-α, IL-1, and IL-7. Understanding the complex molecular mechanisms facilitating cancer cell colonisation and expansion in bone tissues is essential for developing effective treatments to prevent bone metastases . In this review, we discuss current theories linking bone remodelling with bone.

Breast cancer and metastasis to the upper and lower jaws. Review of literature

Breast cancer and metastasis to the upper and lower jaws. Review of literature

Unusual breast metastasis from follicular thyroid carcinoma 17 years after thyroidectomy: a case description and literature analysis.

Unusual breast metastasis from follicular thyroid carcinoma 17 years after thyroidectomy: a case description and literature analysis.

Multimodal treatment paradigm for unstaged resection of a large cystic brain metastasis: illustrative case.

The management of cystic brain metastases remains challenging, with high recurrence rates following treatment with resection and/or stereotactic radiosurgery (SRS). Tumor resection and adjuvant radiation provide superior outcomes in comparison to those for each therapy alone, but large cystic tumor en bloc removal is difficult. Cyst aspiration can be used to decrease the radiation target volume, enabling safer delivery of a therapeutic radiation dose with improved local tumor control. However, cysts can rapidly recur following aspiration. Herein, the authors present a case in which cyst aspiration, radiation, and resection were combined within a single procedure. During a single anesthesia episode, a 70-year-old female underwent stereotactic cyst aspiration, single-fraction SRS, and resection of a 3.7-cm cystic temporal lobe breast metastasis. The lesion volume exceeded 40 cm3 before cyst aspiration, decreasing by 62.5% afterward. Definitive management of large cystic brain metastases including aspiration, radiation, and resection is feasible under a single anesthesia session. This approach, compared to traditional management, could help minimize challenges associated with large cystic lesions, including recurrence and/or radiation necrosis. https://thejns.org/doi/10.3171/CASE24357.

Detection of brain metastases from blood using Brain nanoMET sensor: Extracellular vesicles as a dynamic marker for metastatic brain tumors

Brain metastases account for a significant number of cancer-related deaths with poor prognosis and limited treatment options. Current diagnostic methods have limitations in resolution, sensitivity, inability to differentiate between primary and metastatic brain tumors, and invasiveness. Liquid biopsy is a promising non-invasive alternative; however, current approaches have shown limited efficacy for diagnosing brain metastases due to biomarker instability and low levels of detectable tumor-specific biomarkers. This study introduces an innovative liquid biopsy technique using extracellular vesicles (EVs) as a biomarker for brain metastases, employing the Brain nanoMET sensor. The sensor was fabricated through an ultrashort femtosecond laser ablation process and provides excellent surface-enhanced Raman Scattering functionality. We developed an in vitro model of metastatic tumors to understand the tumor microenvironment and secretomes influencing brain metastases from breast and lung cancers. Molecular profiling of EVs derived from brain-seeking metastatic tumors revealed unique, brain-specific signatures, which were also validated in the peripheral circulation of brain metastasis patients. Compared to primary brain tumor EVs, we also observed an upregulation of PD-L1 marker in the metastatic EVs. A machine learning model trained on these EV molecular profiles achieved 97% sensitivity in differentiating metastatic brain cancer from primary brain cancer, with 94% accuracy in predicting the primary tissue of origin for breast metastasis and 100% accuracy for lung metastasis. The results from this pilot validation suggest that this technique holds significant potential for improving metastasis diagnosis and targeted treatment strategies for brain metastases, addressing a critical unmet need in neuro-oncology.

Breast metastasis from primary renal cell carcinoma, ten years after nephrectomy

BackgroundMetastasis to the breast from non-breast tumors is uncommon, and breast metastasis from renal cell carcinoma (RCC) is extremely rare. Despite the high incidence of primary breast cancer, it is important to consider metastasis from other cancers in patients with a history of malignancies.Case presentationA 60-year-old female with a history of right nephrectomy for RCC 10 years prior, who had missed follow-up for 7 years, presented with hepatic metastases that had been under treatment for the past 2 years. During routine follow-up, a small lesion in her right breast was incidentally found on chest-computed tomography. She was referred for further imaging, and mammography and ultrasound revealed a BI-RADS 3 lesion. Six months later, the lesion had grown rapidly, and a follow-up CT showed a tripling in size along with an increase in the size and number of hepatic metastases. A biopsy of the breast lesion confirmed it as metastatic RCC.ConclusionsThis case is unusual due to the rare site of metastatic spread. Physicians should be aware of considering metastasis when new breast lesions appear in patients with a history of RCC. A biopsy should be considered essential in such cases to ensure accurate diagnosis.

Abstract A035: Infection of primary mammary fibroblasts with cytomegalovirus coordinately increases autotaxin-lysophosphatidate-inflammatory signaling, which could increase breast cancer metastasis

Abstract Background: Metastatic breast cancer is the most prevalent cause of mortality by cancer-related deaths in women. Our group showed that the 63% of Canadian breast cancer patients who were infected with CMV were 5.6-times more likely to develop Stage IV cancers with reduced relapse-free survival. Also, the metastatic phenotype of breast tumors and the number and sizes of lung metastases were increased in mice with latent infections. Fibroblasts are important sites of CMV infection. Cancer-associated fibroblasts (CAFs) are also major sites of autotaxin (ATX) secretion in breast tumors, whereas ATX production and CMV infection in breast cancer cells is negligible. ATX produces lysophosphatidate (LPA), which increases inflammatory cytokine production that stimulates further ATX secretion in a feedforward cycle. LPA promotes breast tumor growth and metastasis by signaling through six G protein-coupled receptors. Signaling is terminated by lipid phosphate phosphatases (LPPs)-1 and -3, which degrade LPA and are decreased in breast tumors. Hypothesis: Breast cancer metastasis could be increased by active CMV infection of CAFs through increased inflammation and LPA signaling. Results: Quiescent fibroblasts isolated and cultured from mammary tissue of non-tumor bearing mice (n&amp;gt;3) produced negligible quantities of ATX. LPA signaling was coordinately promoted in these primary fibroblasts infected for 48 h with 1 MOI of mouse CMV (n=3) with a 5-fold increase in mRNA for ATX (p=0.008), increased mRNAs for LPA2,3,4 receptors (p&amp;lt;0.05) and decreased mRNA expressions for LPP1 and LPP3 (p&amp;lt;0.05). An increase in the secretion of granulocyte monocyte-colony stimulating factor of 548 pg/ml (p=0.01) and Interleukin-6 by 8307 pg/ml (p=0.03) was observed post infection (n=5), thus creating a pro-inflammatory environment. Increased mRNA expression of fibroblast markers, including alpha-smooth muscle actin (p=0.005), fibroblast-associated protein (p=0.007), epidermal growth factor receptor (EGFR) (p=0.001) and transforming growth factor- ß receptor 1 (TGF-ßR1) (p=0.03) was also observed post-infection (n=3). The results were analyzed by student’s t-test. Assessment of these factors in breast cancer patients (n=1100) using the Tumor Immune Estimation Resource Analysis showed a positive correlation in the expression of EGFR and TGF-ßR1 with the LPA3,4 receptors (p&amp;lt;0.05). Conclusion: The changes in expression of ATX, LPA receptors and LPPs in CMV- infected fibroblasts are consistent with increased metastasis. Our results show that mCMV infection of primary mammary fibroblasts dramatically reprograms them to express CAF-like properties and promotes ATX-LPA-inflammatory signaling. CAFs are a major constituent of the tumor stroma. They promote tumor progression by secreting factors such as ATX, which increases metastasis, fibrosis and favors immunosuppression. Our results support the use of pharmacological agents to block signaling by the ATX-LPA-inflammatory cycle to treat breast and other cancers, especially for the majority of patients who are infected with CMV. Citation Format: Humayara Khan, Xiaoyun Tang, Frank Wuest, David N. Brindley, Denise G. Hemmings. Infection of primary mammary fibroblasts with cytomegalovirus coordinately increases autotaxin-lysophosphatidate-inflammatory signaling, which could increase breast cancer metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A035.

Optimizing Drug Delivery to the Brain for Breast Metastasis: A Novel Method for Tumor Targeting.

Brain metastases are difficult to treat due to the blood-brain barrier limiting the delivery of therapeutic agents to the brain effectively. Intraventricular drug delivery has not been well studied for intra-axial pathologies. However, our prior work demonstrated that intraventricular drug delivery in a hyperosmolar vehicle showed preferential accumulation of drug within breast cancer tissue compared to surrounding brain parenchyma. The focus of this study was to explore the molecular parameters of intraventricular drug administration that may optimize drug delivery to intra-axial brain metastases. Our hypothesis was that a low molecular weight drug with a high osmolarity solution would increase drug delivery to tumor tissue. We used an intracerebral breast cancer tumor model in adult female nude rats divided into six experimental groups. We examined three iron-labeled dextran molecules (3 kD, 5 kD, and 10 kD) in 337 mOsm/L solution and three different osmolarities of delivery solution (307, 353, and 368 mOsm/L) with 10 kD dextran. 7T magnetic resonance imaging (MRI) was used to analyze dextran distribution at different time points. All animals were sacrificed after two hours, and the quantity of dextran particles was determined by histopathology. Breast cancer tumor cells were successfully implanted in all rats. The MRI quantification of dextran concentration was well corroborated by histopathology. Varying the molecular size of dextran resulted in the smallest molecule reaching peak levels in tumor tissue earlier than the larger molecules, but the larger molecules remained concentrated in tumor tissue for a longer time. Varying the osmolarity of the delivery solution resulted in the preferential accumulation of 10 kD dextran in tumor tissue except for when dextran was delivered in 368 mOsm/L solution where no preferential distribution was seen. Hyperosmolar intraventricular delivery of chemotherapeutic drugs could be effective in preferentially delivering drugs to abnormal tumor tissues.

Breast metastasis from large cell neuroendocrine carcinoma of the lung: a case report

BackgroundPrimary breast carcinoma is far more common than breast metastases. Common breast metastases usually come from lymphoma, leukemia, melanoma, and ovarian cancers. Breast metastases from neuroendocrine carcinomas are considered an exceeding rare entity. It has been reported in the literature that the pathological presentation of this particular metastatic tumor is very challenging as it shares many morphological characteristics with primary breast carcinoma.Case presentationWe report a case of a patient with large cell neuroendocrine carcinoma of the lung metastasizes to both breasts. The patient was initially presented with brain metastasis of unknown origin. Further radiological imaging workup showed multiple bilateral breast masses and bilateral lymphadenopathy, which raised concern for secondary lymphoma of the breast. The histopathology of this case was challenging, particularly when triple negative invasive ductal carcinoma diagnosis had been made. Multidisciplinary meetings between medical oncologists, radiologists, and pathologists profoundly helped confirming the diagnosis of metastatic large cell neuroendocrine tumor to the breast.ConclusionLarge cell neuroendocrine carcinoma of the lung is a relatively uncommon diagnosis with generally poor prognosis. Large cell neuroendocrine carcinoma that metastasizes to the breast is even scarcer. Correlation between clinical assessment, radiological imaging, and pathological evaluation is the key in making such an unusual and complex diagnosis. Additionally, radiologists should be aware of metastatic presentations of the breast and avoid confusion with mimicking benign entities or primary breast carcinomas.

NSDHL contributes to breast cancer stem-like cell maintenance and tumor-initiating capacity through TGF-β/Smad signaling pathway in MCF-7 tumor spheroid

BackgroundNAD(P)-dependent steroid dehydrogenase-like protein (NSDHL), which is involved in breast tumor growth and metastasis, has been implicated in the maintenance of cancer stem cells. However, its role in regulating breast cancer stem-like cells (BCSCs) remains unclear. We have previously reported the clinical significance of NSDHL in patients with estrogen receptor-positive (ER +) breast cancer. This study aimed to elucidate the molecular mechanisms by which NSDHL regulates the capacity of BCSCs in the ER + human breast cancer cell line, MCF-7.MethodsNSDHL knockdown suppressed tumor spheroid formation in MCF-7 human breast cancer cells grown on ultralow-attachment plates. RNA sequencing revealed that NSDHL knockdown induced widespread transcriptional changes in the MCF-7 spheroids. TGF-β signaling pathway was the most significantly enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway (fold change ≥ 2, P ≤ 0.05) identified in NSDHL-knockdown MCF-7 spheroids compared with the control. In orthotopic tumor models injected with NSDHL-knockdown MCF-7 spheroids, tumor initiation and growth were strongly suppressed compared with those in the control.ResultsBCSC populations with CD44+/CD24- and CD49f+/EpCAM + phenotypes and high ALDH activity were decreased in NSDHL-knockdown MCF-7 spheroids and xenograft tumors relative to controls, along with decreased secretion of TGF-β1 and 3, phosphorylation of Smad2/3, and expression of SOX2. In RNA-sequencing data from The (TCGA) database, a positive correlation between the expression of NSDHL and SOX2 was found in luminal-type breast cancer specimens (n = 998). Our findings revealed that NSDHL plays an important role in maintaining the BCSC population and tumor-initiating capacity of ER-positive MCF-7 spheroids, suggesting that NSDHL is an attractive therapeutic target for eliminating BCSCs, thus preventing breast cancer initiation and progression.ConclusionsOur findings suggest that NSDHL regulates the BCSC/tumor-initiating cell population in MCF-7 spheroids and xenograft tumors.

Screening and validating the optimal panel of housekeeping genes for 4T1 breast carcinoma and metastasis studies in mice

The 4T1 model is extensively employed in murine studies to elucidate the mechanisms underlying the carcinogenesis of triple-negative breast cancer. Molecular biology serves as a cornerstone in these investigations. However, accurate gene expression analyses necessitate data normalization employing housekeeping genes (HKGs) to avert spurious results. Here, we initially delve into the characteristics of the tumor evolution induced by 4T1 in mice, underscoring the imperative for additional tools for tumor monitoring and assessment methods for tracking the animals, thereby facilitating prospective studies employing this methodology. Subsequently, leveraging various software platforms, we assessed ten distinct HKGs (GAPDH, 18 S, ACTB, HPRT1, B2M, GUSB, PGK1, CCSER2, SYMPK, ANKRD17) not hitherto evaluated in the 4T1 breast cancer model, across tumors and diverse tissues afflicted by metastasis. Our principal findings underscore GAPDH as the optimal HKG for gene expression analyses in tumors, while HPRT1 emerged as the most stable in the liver and CCSER2 in the lung. These genes demonstrated consistent expression and minimal variation among experimental groups. Furthermore, employing these HKGs for normalization, we assessed TNF-α and VEGF expression in tissues and discerned significant disparities among groups. We posit that this constitutes the inaugural delineation of an ideal HKG for experiments utilizing the 4T1 model, particularly in vivo settings.

Cisplatin-functionalized dual-functional bone substitute granules for bone defect treatment after bone tumor resection

Invasive bone tumors pose a significant healthcare challenge, often requiring systemic chemotherapy and limb salvage surgery. However, these strategies are hampered by severe side effects, complex post-resection bone defects, and high local recurrence rates. To address this, we developed dual-functional bone substitute biomaterials by functionalizing commercially available bone substitute granules (Bio-Oss® and MBCP®+) with the established anticancer agent cisplatin. Physicochemical characterization revealed that Bio-Oss® granules possess a higher surface area and lower crystallinity compared to MBCP®+ granules, which enhances their capacity for cisplatin adsorption and release. In co-cultures with metastatic breast and prostate cancer cells (MDA-MB-231 and PC3) and bone marrow stromal cells (hBMSCs), cisplatin-functionalized granules and their releasates exhibited dose-dependent cytotoxic effects on cancer cells while having less impact on hBMSCs. Furthermore, investigations on the mechanism of action indicated that cisplatin induced significant cell cycle arrest and apoptosis in MDA-MB-231 and PC3 cells, contrasting with minimal effects on hBMSCs. In a rat femoral condyle defect model, cisplatin-functionalized granules did not evoke adverse effects on bone tissue ingrowth or new bone formation. Importantly, local application of cisplatin-functionalized granules resulted in negligible cisplatin accumulation without signs of apoptotic damage in kidneys and livers. Taken together, we here provide hard evidence that cisplatin-functionalized granules maintain a favorable balance between biosafety, anticancer efficacy, and bone regenerative capacity. Consequently, loading granular bone substitutes with cisplatin holds promise for local treatment of bone defects following bone tumor resections, presenting a safe and potentially more effective alternative to systemic cisplatin administration. Statement of SignificanceCurrent treatments in combating malignant bone tumors are hampered by severe side effects, high local tumor recurrence, and complex bone defects after surgery. This study explores a facile manufacturing method to render two types of commercially available bone substitute granules (Bio-Oss® and MBCP®+) suitable for local delivery of cisplatin. The use of cisplatin-functionalized granules has shown promising results both in killing cancer cells in a dose-dependent manner and in aiding bone regeneration. Importantly, this local treatment strategy avoids the systemic toxicity associated with traditional chemotherapy to excretory organs. This dual-functional strategy represents a significant advancement in bone cancer treatment, offering a safe and more efficient alternative that could improve outcomes for patients following bone tumor resection.

Incidence of a Positive Sentinel Lymph Node Biopsy in Screen-Detected Early Breast Cancer.

Introduction Current guidelines advocate for a sentinel lymph node biopsy (SLNB) in patients with invasive breast cancer with negative axillary ultrasonography. However, emerging evidence has contradicted this, and SLNB omission has been found to be non-inferior in selected low-risk breast cancers. This retrospective study aimed to evaluate the incidence of SLNB in screen-detected invasive breast cancer. The secondary outcome was to identify risk factors in patients with positive SLNB and further axillary disease. Methods All screen-detected histologically confirmed invasive breast cancer and no evidence of spread to ipsilateral axillary lymph nodes (LNs) on ultrasound scans referred from screening between January 2018 and December 2019 were included in the study. All patients underwent surgical excision of the tumor as either breast conservation surgery or mastectomy, along with sentinel node biopsy. SLNB was performed using the dual technique of radioactive dye and blue dye. Results One hundred forty-nine patients were included in the study, all of whom were females. The mean patient age was 61.9 years old, with the majority 65 (43.6%) of the patients being in their 60s. Breast-conserving surgery (BCS) was performed in 138 (92.6%)patients. Eighty (53.7%) patients presented with right breast cancer. The mean size of invasive cancer was 15 mm. The mean total tumor size, including invasive and in situ, was 20.9 mm. One hundred twenty-seven (85.2%)patients had unifocal presentations, 69 (46.3%) oftumor foci were in the upper outer quadrant (UOQ), 122 (81.9%) of all tumors were ductal carcinoma, 81 (54.4%)patients had histologically grade 2 carcinomas, 135 (90.6%) of all patient tumors were ER-positive, HER2-negative, and six (4%) were ER-positive, HER2-positive. Twelve (8.05%) out of 149 included patients had positive sentinel LN biopsy. Of those 12 patients, eight (66.7%) had one to two nodes sampled, three (25%) had three to four nodes, and one (8.3%)had five or more nodes sampled. Out of 12 positive SNB patients, 11 had completed axillary node clearance (ANC) as per the National Institute for Health and Care Excellence (NICE) guidelines: nine (81.8%) had no further disease, and two (18.2%) had four positive nodes. The mean number of nodes taken in ANC was 15.8± 11.5. Of the two patients with positive axillary disease, one had BCS, and the other had a mastectomy. Both were grade 3 IDC, and the mean size was 57.5 mm. Nine patients died within four years of diagnosis, with four due to distant breast metastasis. Conclusion Only 8% of patients had positive SLNB in screen-detected breast cancer, which may supportthe previous studies of omitting SLNB being non-inferior but only in selected postmenopausal small early breast cancers with normal axillary ultrasound in the absence of any other risk factors. However, close follow-up will be required for disease-free survival, overall survival, and locoregional recurrence in this cohort.