scholarly journals Personalized models of breast cancer desmoplasia reveal biomechanical determinants of drug penetration

2021 ◽  
Author(s):  
Giovanni S Offeddu ◽  
Kristina Haase ◽  
Zhengpeng Wan ◽  
Luca Possenti ◽  
Huu Tuan Nguyen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Vascular Dysfunction ◽  
Fluid Pressure ◽  
Drug Distribution ◽  
Drug Efficacy ◽  
Patient Specific ◽  
Breast Cancer Patients ◽  
Disease Mortality ◽  
Key Aspects

Breast cancer desmoplasia heterogeneity contributes to high disease mortality due to discrepancies in treatment efficacy between patients. Personalized in vitro breast cancer models can be used for high throughput testing and ranking of therapeutic strategies to normalize the aberrant microenvironment in a patient-specific manner. Here, tumoroids assembled from patient-derived cells cultured in microphysiological systems including perfusable microvasculature reproduce key aspects of stromal and vascular dysfunction. Increased hyaluronic acid and collagen deposition, loss of vascular glycocalyx and reduced perfusion, and elevated interstitial fluid pressure in the models result in impaired drug distribution to tumor cells. We demonstrate the application of these personalized models as tools to rank molecular therapies for the normalization of the tumoroid microenvironment and to discover new therapeutic targets such as IL8 and CD44, which may ultimately improve drug efficacy in breast cancer patients.

scholarly journals Facilitating Drug Discovery in Breast Cancer by Virtually Screening Patients Using In Vitro Drug Response Modeling

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 885
Author(s):  
Robert F. Gruener ◽  
Alexander Ling ◽  
Ya-Fang Chang ◽  
Gladys Morrison ◽  
Paul Geeleher ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Discovery ◽  
Cell Line ◽  
Drug Response ◽  
Drug Efficacy ◽  
Standard Of Care ◽  
Breast Cancer Patients ◽  
Response Modeling

(1) Background: Drug imputation methods often aim to translate in vitro drug response to in vivo drug efficacy predictions. While commonly used in retrospective analyses, our aim is to investigate the use of drug prediction methods for the generation of novel drug discovery hypotheses. Triple-negative breast cancer (TNBC) is a severe clinical challenge in need of new therapies. (2) Methods: We used an established machine learning approach to build models of drug response based on cell line transcriptome data, which we then applied to patient tumor data to obtain predicted sensitivity scores for hundreds of drugs in over 1000 breast cancer patients. We then examined the relationships between predicted drug response and patient clinical features. (3) Results: Our analysis recapitulated several suspected vulnerabilities in TNBC and identified a number of compounds-of-interest. AZD-1775, a Wee1 inhibitor, was predicted to have preferential activity in TNBC (p < 2.2 × 10−16) and its efficacy was highly associated with TP53 mutations (p = 1.2 × 10−46). We validated these findings using independent cell line screening data and pathway analysis. Additionally, co-administration of AZD-1775 with standard-of-care paclitaxel was able to inhibit tumor growth (p < 0.05) and increase survival (p < 0.01) in a xenograft mouse model of TNBC. (4) Conclusions: Overall, this study provides a framework to turn any cancer transcriptomic dataset into a dataset for drug discovery. Using this framework, one can quickly generate meaningful drug discovery hypotheses for a cancer population of interest.

Targeting PKM2 promotes chemosensitivity of breast cancer cells in vitro and in vivo

2021 ◽  
pp. 1-10
Author(s):  
Yu Wang ◽  
Han Zhao ◽  
Ping Zhao ◽  
Xingang Wang
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Poor Prognosis ◽  
Breast Cancer Cells ◽  
Breast Cancer Patients ◽  
Cancer Tissues

BACKGROUND: Pyruvate kinase M2 (PKM2) was overexpressed in many cancers, and high PKM2 expression was related with poor prognosis and chemoresistance. OBJECTIVE: We investigated the expression of PKM2 in breast cancer and analyzed the relation of PKM2 expression with chemotherapy resistance to the neoadjuvant chemotherapy (NAC). We also investigated whether PKM2 could reverse chemoresistance in breast cancer cells in vitro and in vivo. METHODS: Immunohistochemistry (IHC) was performed in 130 surgical resected breast cancer tissues. 78 core needle biopsies were collected from breast cancer patients before neoadjuvant chemotherapy. The relation of PKM2 expression and multi-drug resistance to NAC was compared. The effect of PKM2 silencing or overexpression on Doxorubicin (DOX) sensitivity in the MCF-7 cells in vitro and in vivo was compared. RESULTS: PKM2 was intensively expressed in breast cancer tissues compared to adjacent normal tissues. In addition, high expression of PKM2 was associated with poor prognosis in breast cancer patients. The NAC patients with high PKM2 expression had short survival. PKM2 was an independent prognostic predictor for surgical resected breast cancer and NAC patients. High PKM2 expression was correlated with neoadjuvant treatment resistance. High PKM2 expression significantly distinguished chemoresistant patients from chemosensitive patients. In vitro and in vivo knockdown of PKM2 expression decreases the resistance to DOX in breast cancer cells in vitro and tumors in vivo. CONCLUSION: PKM2 expression was associated with chemoresistance of breast cancers, and could be used to predict the chemosensitivity. Furthermore, targeting PKM2 could reverse chemoresistance, which provides an effective treatment methods for patients with breast cancer.

scholarly journals A novel hypoxic long noncoding RNA KB-1980E6.3 maintains breast cancer stem cell stemness via interacting with IGF2BP1 to facilitate c-Myc mRNA stability

Oncogene ◽  
2021 ◽  
Author(s):  
Pengpeng Zhu ◽  
Fang He ◽  
Yixuan Hou ◽  
Gang Tu ◽  
Qiao Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Underlying Mechanism ◽  
Rapid Expansion ◽  
Breast Cancer Patients ◽  
Coding Region ◽  
Signaling Axis

AbstractThe hostile hypoxic microenvironment takes primary responsibility for the rapid expansion of breast cancer tumors. However, the underlying mechanism is not fully understood. Here, using RNA sequencing (RNA-seq) analysis, we identified a hypoxia-induced long noncoding RNA (lncRNA) KB-1980E6.3, which is aberrantly upregulated in clinical breast cancer tissues and closely correlated with poor prognosis of breast cancer patients. The enhanced lncRNA KB-1980E6.3 facilitates breast cancer stem cells (BCSCs) self-renewal and tumorigenesis under hypoxic microenvironment both in vitro and in vivo. Mechanistically, lncRNA KB-1980E6.3 recruited insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) to form a lncRNA KB-1980E6.3/IGF2BP1/c-Myc signaling axis that retained the stability of c-Myc mRNA through increasing binding of IGF2BP1 with m6A-modified c-Myc coding region instability determinant (CRD) mRNA. In conclusion, we confirm that lncRNA KB-1980E6.3 maintains the stemness of BCSCs through lncRNA KB-1980E6.3/IGF2BP1/c-Myc axis and suggest that disrupting this axis might provide a new therapeutic target for refractory hypoxic tumors.

scholarly journals Towards integration of 64Cu-DOTA-trastuzumab PET-CT and MRI with mathematical modeling to predict response to neoadjuvant therapy in HER2 + breast cancer

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Angela M. Jarrett ◽  
David A. Hormuth ◽  
Vikram Adhikarla ◽  
Prativa Sahoo ◽  
Daniel Abler ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Targeted Therapy ◽  
Treatment Response ◽  
Growth Factor Receptor ◽  
Patient Specific ◽  
Mathematical Framework ◽  
Breast Cancer Patients ◽  
Data Types ◽  
Her2 Breast Cancer ◽  
Mri Scans

AbstractWhile targeted therapies exist for human epidermal growth factor receptor 2 positive (HER2 +) breast cancer, HER2 + patients do not always respond to therapy. We present the results of utilizing a biophysical mathematical model to predict tumor response for two HER2 + breast cancer patients treated with the same therapeutic regimen but who achieved different treatment outcomes. Quantitative data from magnetic resonance imaging (MRI) and 64Cu-DOTA-trastuzumab positron emission tomography (PET) are used to estimate tumor density, perfusion, and distribution of HER2-targeted antibodies for each individual patient. MRI and PET data are collected prior to therapy, and follow-up MRI scans are acquired at a midpoint in therapy. Given these data types, we align the data sets to a common image space to enable model calibration. Once the model is parameterized with these data, we forecast treatment response with and without HER2-targeted therapy. By incorporating targeted therapy into the model, the resulting predictions are able to distinguish between the two different patient responses, increasing the difference in tumor volume change between the two patients by > 40%. This work provides a proof-of-concept strategy for processing and integrating PET and MRI modalities into a predictive, clinical-mathematical framework to provide patient-specific predictions of HER2 + treatment response.

scholarly journals Integrin alpha5 in human breast cancer is a mediator of bone metastasis and a therapeutic target for the treatment of osteolytic lesions

Oncogene ◽  
2021 ◽  
Author(s):  
Francesco Pantano ◽  
Martine Croset ◽  
Keltouma Driouch ◽  
Natalia Bednarz-Knoll ◽  
Michele Iuliani ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Marrow ◽  
Bone Metastasis ◽  
Tumor Cell ◽  
Cancer Patients ◽  
Breast Cancer Patients ◽  
Osteolytic Lesions ◽  
Cell Colonization

AbstractBone metastasis remains a major cause of mortality and morbidity in breast cancer. Therefore, there is an urgent need to better select high-risk patients in order to adapt patient’s treatment and prevent bone recurrence. Here, we found that integrin alpha5 (ITGA5) was highly expressed in bone metastases, compared to lung, liver, or brain metastases. High ITGA5 expression in primary tumors correlated with the presence of disseminated tumor cells in bone marrow aspirates from early stage breast cancer patients (n = 268; p = 0.039). ITGA5 was also predictive of poor bone metastasis-free survival in two separate clinical data sets (n = 855, HR = 1.36, p = 0.018 and n = 427, HR = 1.62, p = 0.024). This prognostic value remained significant in multivariate analysis (p = 0.028). Experimentally, ITGA5 silencing impaired tumor cell adhesion to fibronectin, migration, and survival. ITGA5 silencing also reduced tumor cell colonization of the bone marrow and formation of osteolytic lesions in vivo. Conversely, ITGA5 overexpression promoted bone metastasis. Pharmacological inhibition of ITGA5 with humanized monoclonal antibody M200 (volociximab) recapitulated inhibitory effects of ITGA5 silencing on tumor cell functions in vitro and tumor cell colonization of the bone marrow in vivo. M200 also markedly reduced tumor outgrowth in experimental models of bone metastasis or tumorigenesis, and blunted cancer-associated bone destruction. ITGA5 was not only expressed by tumor cells but also osteoclasts. In this respect, M200 decreased human osteoclast-mediated bone resorption in vitro. Overall, this study identifies ITGA5 as a mediator of breast-to-bone metastasis and raises the possibility that volociximab/M200 could be repurposed for the treatment of ITGA5-positive breast cancer patients with bone metastases.

scholarly journals Twist-mediated PAR1 induction is required for breast cancer progression and metastasis by inhibiting Hippo pathway

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Yifan Wang ◽  
Ruocen Liao ◽  
Xingyu Chen ◽  
Xuhua Ying ◽  
Guanping Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Invasive Breast Cancer ◽  
Breast Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Hippo Pathway ◽  
Breast Cancer Patients ◽  
Mesenchymal Transition

Abstract Breast cancer is considered to be the most prevalent cancer in women worldwide, and metastasis is the primary cause of death. Protease-activated receptor 1 (PAR1) is a GPCR family member involved in the invasive and metastatic processes of cancer cells. However, the functions and underlying mechanisms of PAR1 in breast cancer remain unclear. In this study, we found that PAR1 is highly expressed in high invasive breast cancer cells, and predicts poor prognosis in ER-negative and high-grade breast cancer patients. Mechanistically, Twist transcriptionally induces PAR1 expression, leading to inhibition of Hippo pathway and activation of YAP/TAZ; Inhibition of PAR1 suppresses YAP/TAZ-induced epithelial-mesenchymal transition (EMT), invasion, migration, cancer stem cell (CSC)-like properties, tumor growth and metastasis of breast cancer cells in vitro and in vivo. These findings suggest that PAR1 acts as a direct transcriptionally target of Twist, can promote EMT, tumorigenicity and metastasis by controlling the Hippo pathway; this may lead to a potential therapeutic target for treating invasive breast cancer.

scholarly journals Letrozole Accelerates Metabolic Remodeling through Activation of Glycolysis in Cardiomyocytes: A Role beyond Hormone Regulation

2022 ◽  
Vol 23 (1) ◽  
pp. 547
Author(s):  
Jun H. Heo ◽  
Sang R. Lee ◽  
Seong Lae Jo ◽  
Hyun Yang ◽  
Hye Won Lee ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lipid Metabolism ◽  
Cancer Patients ◽  
Cardiovascular Effects ◽  
Female Rats ◽  
Acid Oxidation ◽  
Hormone Regulation ◽  
Breast Cancer Patients ◽  
Metabolic Remodeling

Estrogen receptor-positive (ER+) breast cancer patients are recommended hormone therapy as a primary adjuvant treatment after surgery. Aromatase inhibitors (AIs) are widely administered to ER+ breast cancer patients as estrogen blockers; however, their safety remains controversial. The use of letrozole, an AI, has been reported to cause adverse cardiovascular effects. We aimed to elucidate the effects of letrozole on the cardiovascular system. Female rats exposed to letrozole for four weeks showed metabolic changes, i.e., decreased fatty acid oxidation, increased glycolysis, and hypertrophy in the left ventricle. Although lipid oxidation yields more ATP than carbohydrate metabolism, the latter predominates in the heart under pathological conditions. Reduced lipid metabolism is attributed to reduced β-oxidation due to low circulating estrogen levels. In letrozole-treated rats, glycolysis levels were found to be increased in the heart. Furthermore, the levels of glycolytic enzymes were increased (in a high glucose medium) and the glycolytic rate was increased in vitro (H9c2 cells); the same was not true in the case of estrogen treatment. Reduced lipid metabolism and increased glycolysis can lower energy supply to the heart, resulting in predisposition to heart failure. These data suggest that a letrozole-induced cardiac metabolic remodeling, i.e., a shift from β-oxidation to glycolysis, may induce cardiac structural remodeling.

scholarly journals Oleanolic Acid’s Semisynthetic Derivatives HIMOXOL and Br-HIMOLID Show Proautophagic Potential and Inhibit Migration of HER2-Positive Breast Cancer Cells In Vitro

2021 ◽  
Vol 22 (20) ◽  
pp. 11273
Author(s):  
Natalia Magdalena Lisiak ◽  
Izabela Lewicka ◽  
Mariusz Kaczmarek ◽  
Jacek Kujawski ◽  
Barbara Bednarczyk-Cwynar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Biological Activity ◽  
Cancer Cells ◽  
Oleanolic Acid ◽  
Breast Cancer Cells ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

Approximately 20–30% of the diagnosed breast cancers overexpress the human epidermal growth factor receptor 2 (HER2). This type of cancer is associated with a more aggressive phenotype; thus, there is a need for the discovery of new compounds that would improve the survival in HER2-positive breast cancer patients. It seems that one of the most promising therapeutic cancer strategies could be based on the biological activity of pentacyclic triterpenes’ derivatives and the best-known representative of this group, oleanolic acid (OA). The biological activity of oleanolic acid and its two semisynthetic derivatives, methyl 3-hydroxyimino-11-oxoolean-12-en-28-oate (HIMOXOL) and 12α-bromo-3-hydroxyimonoolean-28→13-olide (Br-HIMOLID), was assessed in SK-BR-3 breast cancer cells (HER2-positive). Viability tests, cell cycle assessment, evaluation of apoptosis, autophagy, and adhesion/migration processes were performed using MTT, clonogenic, cytofluorometry, Western blot, and qPCR. Both derivatives revealed higher cytotoxicity in studied breast cancer cells than the maternal compound, OA. They also decreased cell viability, induced autophagy, and (when applied in sub-cytotoxic concentrations) decreased the migration of SK-BR-3 cells.This study is the first to report the cytostatic, proautophagic (mTOR/LC3/SQSTM/BECN1 pathway), and anti-migratory (integrin β1/FAK/paxillin pathway) activities of HIMOXOL and Br-HIMOLID in HER2-positive breast cancer cells.

scholarly journals Enhancers mapping uncovers phenotypic heterogeneity and evolution in patients with luminal breast cancer

2017 ◽  
Author(s):  
Darren K. Patten ◽  
Giacomo Corleone ◽  
Balázs Győrffy ◽  
Edina Erdős ◽  
Alina Saiakhova ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Regulatory Elements ◽  
Phenotypic Heterogeneity ◽  
Endocrine Treatment ◽  
Clinical Samples ◽  
Luminal Breast Cancer ◽  
Breast Cancer Patients ◽  
Expression Of Genes

AbstractThe degree of intrinsic and interpatient phenotypic heterogeneity and its role in tumour evolution is poorly understood. Phenotypic divergence can be achieved via the inheritance of alternative transcriptional programs1,2. Cell-type specific transcription is maintained through the activation of epigenetically-defined regulatory regions including promoters and enhancers1,3,4. In this work, we annotated the epigenome of 47 primary and metastatic oestrogen-receptor (ERα)-positive breast cancer specimens from clinical samples, and developed strategies to deduce phenotypic heterogeneity from the regulatory landscape, identifying key regulatory elements commonly shared across patients. Highly shared regions contain a unique set of regulatory information including the motif for the transcription factor YY1. In vitro work shows that YY1 is essential for ERα transcriptional activity and defines the critical subset of functional ERα binding sites driving tumor growth in most luminal patients. YY1 also control the expression of genes that mediate resistance to endocrine treatment. Finally, we show that H3K27ac levels at active enhancer elements can be used as a surrogate of intra-tumor phenotypic heterogeneity, and to track expansion and contraction of phenotypic subpopulations throughout breast cancer progression. Tracking YY1 and SLC9A3R1 positive clones in primary and metastatic lesions, we show that endocrine therapies drive the expansion of phenotypic clones originally underrepresented at diagnosis. Collectively, our data show that epigenetic mechanisms significantly contribute to phenotypic heterogeneity and evolution in systemically treated breast cancer patients.

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