Biology subjects

Woodward, W. A.

Publications and source records attributed to Woodward, W. A..

6 recordsLinked to original sources

bioRxiv2024

In Vivo Simvastatin and Brain Radiation in a Model of HER2+ Inflammatory Breast Cancer Brain Metastasis

PurposeInhibiting HMG-CoA reductase with simvastatin prevents breast cancer metastases in preclinical models and radiosensitizes monolayer and stem-like IBC cell lines in vitro. Given the extensive use of simvastatin worldwide and its expected penetration into the brain, we examined whether regulating cholesterol with simvastatin affected IBC3 HER2+ brain metastases. Methods and MaterialsBreast cancer cell lines KPL4 and MDA-IBC3 were examined in vitro for DNA repair after radiation with or without statin treatment. Brain metastasis endpoints were examined in the MDA-IBC3 brain metastasis model after ex vivo exposure to lipoproteins and after tail vein injections with and without whole-brain radiotherapy (WBR) and oral statin exposure. ResultsEx vivo preculture of MDA-IBC3 cells with very low-density lipoprotein (vLDL) enhanced the growth of colonized lesions in the brain in vivo compared with control or high-density lipoprotein (HDL), and concurrent oral simvastatin/ WBR reduced the incidence of micrometastatic lesions evaluated 10 days after WBR. However, statin, with or without WBR, did not reduce the incidence, burden, or number of macrometastatic brain lesions evaluated 5 weeks after WBR. ConclusionsAlthough a role for cholesterol biosynthesis is demonstrated in DNA repair and response to whole brain radiation in this model, durable in vivo efficacy of concurrent whole brain irradiation and oral statin was not demonstrated.

cancer biology↗

bioRxiv2021

Lipocalin 2 promotes inflammatory breast cancer tumorigenesis and skin invasion

Inflammatory breast cancer (IBC) is an aggressive form of primary breast cancer characterized by rapid onset and high risk of metastasis and poor clinical outcomes. The biological basis for the aggressiveness of IBC is still not well understood and no IBC-specific targeted therapies exist. In this study we report that lipocalin 2 (LCN2), a small secreted glycoprotein belonging to the lipocalin superfamily, is expressed at significantly higher levels in IBC versus non-IBC tumors, independently of molecular subtype. LCN2 levels were also significantly higher in IBC cell lines and in their culture media than in non-IBC cell lines. High expression was associated with poor-prognosis features and shorter overall survival in IBC patients. Depletion of LCN2 in IBC cell lines reduced proliferation, colony formation, migration, and cancer stem cell populations in vitro, and inhibited tumor growth, skin invasion, and brain metastasis in mouse models of IBC. Analysis of our proteomics data showed reduced expression of proteins involved in cell cycle and DNA repair in LCN2-silenced IBC cells. Our findings support that LCN2 promotes IBC tumor aggressiveness and offer a new potential therapeutic target for IBC.

cancer biology↗

bioRxiv2020

NDRG1 expression is an independent prognostic factor in inflammatory breast cancer

NDRG1 is widely described as a metastasis suppressor in breast cancer. However, we found that NDRG1 is critical in promoting tumorigenesis and brain metastasis in mouse models of inflammatory breast cancer (IBC), a rare but highly aggressive form of breast cancer. We hypothesized that NDRG1 is a prognostic marker associated with poor outcome in patients with IBC. Microarray gene expression data from the IBC Consortium dataset were analyzed to compare NDRG1 expression between IBC and non-IBC tumors and among breast cancer subtypes. NDRG1 levels in tissue microarrays from 64 IBC patients were evaluated by immunohistochemical staining with anti-NDRG1 primary antibody (32 NDRG1-low [[≤] median], 32 NDRG1-high [>median]). Overall and disease-free survival (OS and DSS) were analyzed with Kaplan-Meier curves and log-rank test. NDRG1 mRNA expression was higher in IBC than in non-IBC tumors (p=0.007), and in more aggressive HER2+ and basal-like vs luminal IBC subtypes (p<0.0001). Univariate analysis showed NDRG1 expression, tumor grade, disease stage, estrogen receptor (ER) status, and receipt of adjuvant radiation to be associated with OS and DSS. NDRG1-high patients had poorer 10-year OS and DSS than NDRG1-low patients (OS, 19% vs 45%, p=0.0278; DSS, 22% vs 52%, p=0.0139). On multivariable analysis, NDRG1 independently predicted OS (hazard ratio [HR]=2.034, p=0.0274) and DSS (HR=2.287, p=0.0174). NDRG1-high ER-negative tumors had worse outcomes OS, p=0.0003; DSS, p=0.0003; and NDRG1-high tumors that received adjuvant radiation treatment had poor outcomes (OS, p=0.0088; DSS, p=0.0093). NDRG1 correlated positively with aggressive tumor characteristics in IBC and was a significant independent prognostic factor for DSS and OSS in IBC patients. Targeting NDRG1 may represent a novel strategy for improving clinical outcomes for patients with IBC.

cancer biology↗

bioRxiv2020

Decorin, a novel negative modulator of E-cadherin in inflammatory breast cancer

ABSTRACTInflammatory breast cancer (IBC) is a clinically distinct and highly aggressive form of breast cancer with rapid onset and a strong propensity to metastasize. The molecular mechanisms underlying the aggressiveness and metastatic propensity of IBC are largely unknown. Herein, we report that decorin (DCN), a small leucine-rich extracellular matrix proteoglycan, is downregulated in tumors from patients with IBC. Overexpression of DCN in IBC cells markedly decreased migration, invasion, and cancer stem cells in vitro and inhibited IBC tumor growth and metastasis in vivo. Mechanistically, DCN functioned as a suppressor of invasion and tumor growth in IBC by destabilizing E-cadherin and inhibiting EGFR/ERK signaling. DCN physically binds E-cadherin in IBC cells and accelerates its degradation through an autophagy-linked lysosomal pathway. We established that DCN inhibits tumorigenesis and metastasis in IBC cells by negatively regulating the E-cadherin/EGFR/ERK axis. Our findings offer a potential therapeutic strategy for IBC, and provide a novel mechanism for IBC pathobiology.Competing Interest StatementThe authors have declared no competing interest.View Full Text

cancer biology↗

bioRxiv2017

Analysis of hierarchical organization in gene expression networks reveals underlying principles of collective tumor cell dissemination and metastatic aggressiveness of inflammatory breast cancer

BackgroundClusters of circulating tumor cells (CTCs), despite being rare, may account for more than 95% of metastases. Cells in these clusters do not undergo a complete epithelial-to-mesenchymal transition (EMT) but retain some epithelial traits as compared to individually disseminating tumor cells. Determinants of single cell dissemination versus collective dissemination remain elusive. Inflammatory breast cancer (IBC), a highly aggressive breast cancer subtype that chiefly metastasizes via CTC clusters, is a promising model for studying mechanisms of collective tumor cell dissemination. Previous studies on breast cancer and adult acute myeloid leukemia, motivated by a theory that suggests physical systems with hierarchical organization tend to be more adaptable, have found that the expression of metastasis associated genes is more hierarchically organized in cases of successful metastases.\n\nMethodsWe used the cophenetic correlation coefficient (CCC) to quantify the hierarchical organization in the expression networks of two distinct gene sets, collective dissemination associated genes and IBC associated genes, in cancer cell lines and in tumor samples from breast cancer patients. Hypothesizing that a higher CCC for collective dissemination associated genes and for IBC associated genes would be associated with a more evident epithelial phenotype and with worse outcomes in breast cancer patients, we evaluated the correlation of CCC with different phenotypic groups.\n\nResultsThe CCC of both gene networks, the collective dissemination associated gene network and the IBC associated gene network, was higher in (a) epithelial cell lines as compared to mesenchymal cell lines and (b) tumor samples from IBC patients, as compared to samples from non-IBC breast cancer patients. A higher CCC of both networks was also correlated with a higher rate of metastatic relapse in breast cancer patients. Neither the levels of CDH1 gene expression, nor gene set enrichment analysis could provide similar insights.\n\nConclusionsThese results suggest that retention of some epithelial traits in disseminating tumor cells as IBC progresses promotes successful breast cancer metastasis to distant organs. The CCC provides additional information regarding the organizational complexity of gene expression in comparison to differential gene expression analyses. We have shown that the CCC may be a useful metric for investigating the collective dissemination phenotype and a prognostic factor for IBC.

cancer biology↗

bioRxiv2017

Inflammatory Breast Cancer: a model for investigating cluster-based dissemination

Metastases claim more than 90% of cancer-related patient deaths and are usually seeded by a subset of circulating tumor cells (CTCs) shed off from the primary tumor. In circulation, CTCs are found both as single cells and as clusters of cells. The clusters of CTCs, although many fewer in number, possess much higher metastatic potential as compared to that of individual CTCs. In this review, we highlight recent insights into molecular mechanisms that can enable the formation of these clusters - (a) hybrid epithelial/mesenchymal (E/M) phenotype of cells that couples their ability to migrate and adhere, and (b) intercellular communication that can spatially coordinate the cluster formation and provide survival signals to cancer cells. Building upon these molecular mechanisms, we also offer a possible mechanistic understanding of why clusters are endowed with a higher metastatic potential. Finally, we discuss the highly aggressive Inflammatory Breast Cancer (IBC) as an example of a carcinoma that can metastasize via clusters and corroborates the proposed molecular mechanisms.

cancer biology↗