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Postdoc, University of Iowa

PINBOARD SUMMARY

Defining the mechanism of action of antiviral factors and how they promote breast malignancies

Breast cancer (BC) is the second cause of cancer-related deaths in women. Only 26% of metastatic BC patients will survive past 5 years partially due to lack of effective treatments. Thus, there is a need to discover new therapeutic targets. Bone marrow stromal antigen 2 (BST-2) is a newly discovered cancer-promoting gene which induces invasion, adhesion, spheroidization, and anchorage-independent growth (AIG). Orthotopic implantation of BST-2-expressing cancer cells resulted in poor survival due to metastasis. While BST-2 promotes a plethora of cancer phenotypes, the exact mechanism by which BST-2 promotes these effects remained elusive. To investigate how BST-2 promotes cancer cell adhesion and AIG, we generated BC cells stably overexpressing wild-type or interaction-deficient BST-2. These cells were used in vitro to assess cell adhesion, AIG, invasion, and anoikis resistance; and, in vivo to analyze primary tumor growth, metastasis, and host survival. We also generated a molecule (M1) which targets the BST-2 preventing interactions with itself in cancer cells. The aforementioned in vitro assays were used to assess M1 as a potential therapeutic lead for BST-2-dependent BCs. We report that BST-2 interactions are necessary for homotypic and heterotypic adhesion and anoikis resistance, resulting in efficient spheroid formation and AIG. The effects of BST-2 interactions in vivo are increased primary tumor growth, metastasis, and decreased host survival. Interestingly, M1prevented cancer cell adhesion and growth in vitro independent of subtype classification and reduced breast tumor growth in vivo. BST-2 interactions promote cancer cell survival and growth by promoting cell clustering, growth and anoikis resistance while M1 averted these cancer-promoting activities. Given that BST-2 expression in BC is subtype independent, we expect M1 to target all BCs that express BST-2. Future experiments will aim at identifying and stabilizing the smallest M1 fragment that retains full anti-cancer activity to increase its effectiveness.

3 ITEMS PINNED

Up-regulation of bone marrow stromal protein 2 (BST2) in breast cancer with bone metastasis.

Abstract: Bone metastases are frequent complications of breast cancer. Recent literature implicates multiple chemokines in the formation of bone metastases in breast cancer. However, the molecular mechanism of metastatic bone disease in breast cancer remains unknown. We have recently made the novel observation of the BST2 protein expression in human breast cancer cell lines. The purpose of our present study is to investigate the expression and the role of BST2 in bone metastatic breast cancer.cDNA microarray analysis was used to compare the BST2 gene expression between a metastatic to bone human breast cancer cell line (MDA-231BO) and a primary human breast cancer cell line (MDA-231). The BST2 expression in one bone metastatic breast cancer and seven non-bone metastatic breast cancer cell lines were also determined using real-time RT-PCR and Western blot assays. We then employed tissue array to further study the BST2 expression in human breast cancer using array slides containing 20 independent breast cancer tumors that formed metastatic bone lesions, 30 non-metastasis-forming breast cancer tumors, and 8 normal breast tissues. In order to test the feasibility of utilizing BST2 as a serum marker for the presence of bone metastasis in breast cancer, we had measured the BST2 expression levels in human serums by using ELISA on 43 breast cancer patients with bone metastasis, 43 breast cancer patients without bone metastasis, and 14 normal healthy controls. The relationship between cell migration and proliferation and BST2 expression was also studied in a human breast recombinant model system using migration and FACS analysis.The microarray demonstrated over expression of the BST2 gene in the bone metastatic breast cancer cell line (MDA-231BO) compared to the primary human breast cancer cell line (MDA-231). The expression of the BST2 gene was significantly increased in the bone metastatic breast cancer cell lines and tumor tissues compared to non-bone metastatic breast cancer cell lines and tumor tissues by real time RT-PCR, Western blot and TMA. Furthermore, serum levels of BST2 measured by ELISA were also significantly higher among patients with breast cancer metastatic to bone compared to breast cancer patients without metastatic to bone (P < .0001). Most importantly, the breast cancer cell line that transfected with BST2 demonstrated increased BST2 expressions, which was associated with increased cancer cell migration and cell proliferation.These results provide novel data indicating the BST2 protein expression is associated with the formation of bone metastases in human breast cancer. We believe that BST2 may be a potential biomarker in breast cancer with bone metastasis.

Pub.: 03 Apr '09, Pinned: 16 Jun '17

Aberrant regulation of the BST2 (Tetherin) promoter enhances cell proliferation and apoptosis evasion in high grade breast cancer cells.

Abstract: Normal cellular phenotypes that serve an oncogenic function during tumorigenesis are potential candidates for cancer targeting drugs. Within a subset of invasive primary breast carcinoma, we observed relatively abundant expression of Tetherin, a cell surface protein encoded by the Bone Marrow Stromal Cell Antigen (BST2) known to play an inhibitory role in viral release from infected immune cells of the host. Using breast cancer cell lines derived from low and intermediate histopathologic grade invasive primary tumors that maintain growth-suppressive TGFβ signaling, we demonstrate that BST2 is negatively regulated by the TGFβ axis in epithelial cells. Binding of the transcription factor AP2 to the BST2 promoter was attenuated by inhibition of the TGFβ pathway thereby increasing BST2 expression in tumor cells. In contrast, inherent TGFβ resistance characteristic of high grade breast tumors is a key factor underlying compromised BST2 regulation, and consequently its constitutive overexpression relative to non-malignant breast epithelium, and to most low and intermediate grade cancer cells. In both 2-dimensional and 3-dimensional growth conditions, BST2-silenced tumor cells displayed an enhancement in tamoxifen or staurosporine-induced apoptotic cell death together with a reduction in the S-phase fraction compared to BST2 overexpressing counterparts. In a subset of breast cancer patients treated with pro apoptotic hormonal therapy, BST2 expression correlated with a trend for poor clinical outcome, further supporting its role in conferring an anti apoptotic phenotype. Similar to the effects of gene manipulation, declining levels of endogenous BST2 induced by the phytoalexin - resveratrol, restored apoptotic function, and curbed cell proliferation. We provide evidence for a direct approach that diminishes aberrant BST2 expression in cancer cells as an early targeting strategy to assist in surmounting resistance to pro apoptotic therapies.

Pub.: 11 Jul '13, Pinned: 16 Jun '17