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Hirotaka Kanzaki,1 Avradip Chatterjee,1 Hanieh Hossein Nejad Ariani,1 Xinfeng Zhang,2 Stacey Chung,2 Nan Deng,3,4 V Krishnan Ramanujan,4 Xiaojiang Cui,1,2,4 Mark I Greene,5 Ramachandran Murali1 1Department of Biomedical Sciences, Research Division of Immunology; 2Department of Surgery; 3Biostatistics and Bioinformatics Research Center; 4Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA; 5Department of Pathology and Laboratory of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USACorrespondence: Ramachandran Murali Email ramachandran.murali@csmc.eduIntroduction: Constitutive activation of NF-κB has been implicated as being contributive to cancer cell growth, drug resistance, and tumor recurrence in many cancers including breast cancer. Activation of NF-κB leads to nuclear translocation of RelA, a critical component of the NF-κB transcription factor complex, which subsequently binds to specific DNA sites and activates a multitude of genes involved in diverse cell functions. Studies show that triple-negative breast cancer (TNBC) cells possess constitutively active NF-κB and concomitantly have higher levels of nuclear localization of RelA than cytoplasmic RelA. This feature is considered to be associated with the response to chemotherapy. However, currently, there is no specific inhibitor to block nuclear translocation of RelA.Methods: A structure-based approach was used to develop a small-molecule inhibitor of RelA nuclear translocation. The interaction between this molecule and RelA was verified biophysically through isothermal titration calorimetry and microscale thermophoresis. TNBC cell lines MDA-MB-231 and MDA-MB-468 and a human TNBC xenograft model were used to verify in vitro and in vivo efficacy of the small molecule, respectively.Results: We found that the small molecule, CRL1101, bound specifically to RelA as indicated by the biophysical assays. Further, CRL1101 blocked RelA nuclear translocation in breast cancer cells in vitro, and markedly reduced breast tumor growth in a triple-negative breast cancer xenograft model.Conclusion: Our study demonstrates that CRL1101 may lead to new NF-κB-targeted therapeutics for TNBC. Further, blocking of nuclear translocation of shuttling transcription factors may be a useful general strategy in cancer drug development.Keywords: transcription factors, breast cancer, computer aided drug design, nuclear transport, drug-target

Granulocytes are key players in cancer metastasis. While tumor-induced de novo expansion of immunosuppressive myeloid-derived suppressor cells (MDSCs) is well-described, the fate and contribution of terminally differentiated mature neutrophils to the metastatic process remain poorly understood. Here, we show that in experimental metastatic cancer models, CXCR4hiCD62Llo aged neutrophils accumulate via disruption of neutrophil circadian homeostasis and direct stimulation of neutrophil aging mediated by angiotensin II. Compared to CXCR4loCD62Lhi naive neutrophils, aged neutrophils more robustly promote tumor migration and support metastasis through the increased release of several metastasis-promoting factors, including neutrophil extracellular traps (NETs), reactive oxygen species, vascular endothelial growth factors, and metalloproteinases (MMP-9). Adoptive transfer of aged neutrophils significantly enhanced metastasis of breast (4T1) and melanoma (B16LS9) cancer cells to the liver, and these effects were predominantly mediated by NETs. Our results highlight that in addition to modulating MDSC production, targeting aged neutrophil clearance and homeostasis may be effective in reducing cancer metastasis.

Distant metastasis accounts for the vast majority of deaths in patients with cancer. Breast cancer exhibits a distinct metastatic pattern commonly involving bone, liver, lung, and brain. Breast cancer can be divided into different subtypes based on gene expression profiles, and different breast cancer subtypes show preference to distinct organ sites of metastasis. Luminal breast tumors tend to metastasize to bone while basal-like breast cancer (BLBC) displays a lung tropism of metastasis. However, the mechanisms underlying this organ-specific pattern of metastasis still remain to be elucidated. In this review, we will summarize the recent advances regarding the molecular signaling pathways as well as the therapeutic strategies for treating breast cancer lung metastasis.

Type I insulin-like growth factor receptor (IGF-IR) can transform mouse fibroblasts; however, little is known about the transforming potential of IGF-IR in human fibroblasts or epithelial cells. We found that overexpression of a constitutively activated IGF-IR (CD8-IGF-IR) was sufficient to cause transformation of immortalized human mammary epithelial cells and growth in immunocompromised mice. Furthermore, CD8-IGF-IR caused cells to undergo an epithelial-to-mesenchymal transition (EMT) which was associated with dramatically increased migration and invasion. The EMT was mediated by the induction of the transcriptional repressor Snail and downregulation of E-cadherin. NF-kappaB was highly active in CD8-IGF-IR-MCF10A cells, and both increased levels of Snail and the EMT were partially reversed by blocking NF-kappaB or IGF-IR activity. This study places IGF-IR among a small group of oncogenes that, when overexpressed alone, can confer in vivo tumorigenic growth of MCF10A cells and indicates the hierarchy in the mechanism of IGF-IR-induced EMT.

Insulin receptor substrates (IRSs) are adaptor proteins that link signaling from upstream activators to multiple downstream effectors to modulate normal growth, metabolism, survival, and differentiation. Recent cell culture studies have shown that IRSs can interact with, and are functionally required for, the transforming ability of many oncogenes. Consistent with this, IRSs are elevated and hyperactive in many human tumors. IRSs respond to many extracellular signals that are critical for mammary gland development, and we have shown that IRSs disrupt normal mammary acini formation in vitro, and cause mammary tumorigenesis and metastasis in vivo. In this review we will discuss the role of IRSs in both transformation and cancer progression.

Houdong Zuo,1 Weiwu Yao,1 Nan Qu,1 Shixun Yang,1 Jianhua Wang,2 Xiaojiang Cui3 1Department of Radiology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, People’s Republic of China; 2Department of Orthopedics, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 3Department of Surgery, Department of Obstetrics and Gynecology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA Purpose: To evaluate quantitative T1and T2relaxation times and magnetization transfer ratios (MTRs) in the early diagnosis of patellar cartilage osteoarthritis (OA) and to quantify and possibly refine the current Kellgren-Lawrence score criteria. Materials and methods: A total of 92cases of knee joints with 40normal volunteers and 30patients with OA were prospectively evaluated. The knee joints with OA were divided into mild and moderate groups according to the Kellgren-Lawrence score criteria. The discriminative analysis method was used to analyze the accuracy of the original grouped cases correctly classified by age, sex, T1relaxation times, T2relaxation times, and MTR values. Linear regression analysis was used between T1relaxation time, T2relaxation time, and MTR values. Results: The mean T1relaxation times decreased with the severity of OA, and a significant difference was only found between the normal and moderate OA groups (P