Project description:Development and pre-clinical testing of new cancer therapies is limited by the scarcity of in vivo models that authentically reproduce tumor growth and metastatic progression. We report new models for breast tumor growth and metastasis, in the form of transplantable tumors derived directly from individuals undergoing treatment for breast cancer. These tumor grafts represent the diversity of human breast cancer and maintain essential features of the original tumors, including metastasis to specific sites. Co-engraftment of primary human mesenchymal stem cells maintains phenotypic stability of the grafts and increases tumor growth by promoting angiogenesis. We also report that tumor engraftment is a prognostic indicator of disease outcome for newly diagnosed women; orthotopic breast tumor grafting marks a step toward individualized models for tumor growth, metastasis, and prognosis. This bank of tumor grafts also serves as a publicly available resource for new models in which to study the biology of breast cancer.
Project description:Development and pre-clinical testing of new cancer therapies is limited by the scarcity of in vivo models that authentically reproduce tumor growth and metastatic progression. We report new models for breast tumor growth and metastasis, in the form of transplantable tumors derived directly from individuals undergoing treatment for breast cancer. These tumor grafts represent the diversity of human breast cancer and maintain essential features of the original tumors, including metastasis to specific sites. Co-engraftment of primary human mesenchymal stem cells maintains phenotypic stability of the grafts and increases tumor growth by promoting angiogenesis. We also report that tumor engraftment is a prognostic indicator of disease outcome for newly diagnosed women; orthotopic breast tumor grafting marks a step toward individualized models for tumor growth, metastasis, and prognosis. This bank of tumor grafts also serves as a publicly available resource for new models in which to study the biology of breast cancer. Single replicates of genomic DNA from 12 human breast cancer tumors and xenografts of those tumors in immunodeficient mice were hybridized to Affymetrix Human SNP 6.0 genotyping arrays.
Project description:Programmed death ligand-1 (PD-L1) is a well-known transmembrane protein, which antibodies present effective clinical therapy in multiple human cancers. However, the function of tumor cell-intrinsic PD-L1 and its related mechanism in breast cancer remains incompletely studied. Programmed death ligand 1 (PD-L1) on the membrane of tumor cells strengthens tumor immune escape. Tumor cell-intrinsic PD-L1 is also involved in tumorigenesis and development, but the mechanism in regulating PD-L1 expression remains incompletely studied. Here, we report a novel mechanism for PD-L1 that can be induced by hepatitis B X-interacting protein (HBXIP), an oncogenic transcriptional coactivator, promoting breast cancer growth. Overexpression of PD-L1 increases breast cancer proliferation in vitro and in vivo. Transcriptomic analysis also reveals that PD-L1 plays a critical role in cancer development. Furthermore, we find that the expression of PD-L1 is positively associated with HBXIP in breast cancer clinical tissues as well as in cell lines, PD-L1 and HBXIP expression have higher levels in tumor. Mechanistically, HBXIP predominantly stimulates the promoter activity of PD-L1 through coactivating transcription factor ETS2. Especially, HBXIP induced PD-L1 acetylation with the acetyltransferase p300 at lysine 270 (K270), enhancing PD-L1 protein stability. Functionally, depletion of HBXIP markedly attenuates PD-L1-induced breast tumor growth in vitro and in vivo. Moreover, aspirin decreased breast cancer growth via targeting PD-L1 and HBXIP. Taken together, our results extend a new mechanism of PD-L1 functions, expound non-immune effects of PD-L1 and imply broader uses for PD-L1 as a target in breast cancer therapy.
Project description:Hepsin, a type II transmembrane serine protease, is commonly overexpressed in prostate and breast cancer. The hepsin protein is stabilized by the Ras-MAPK pathway, and downstream, this protease regulates the degradation of extracellular matrix components and activates growth factor pathways, such as hepatocyte growth factor and transforming growth factor beta (TGFβ) pathway. However, how exactly active hepsin promotes cell proliferation machinery to sustain tumor growth is not fully understood. Here, we show that genetic deletion of Hpn in a WAP-Myc model of aggressive MYC-driven breast cancer inhibits tumor growth in the primary syngrafted sites and the growth of disseminated tumors in the lungs. The suppression of tumor growth upon loss of hepsin was accompanied by downregulation of TGFβ and EGFR signaling together with a reduction in EGFR protein levels. We further demonstrate in 3D cultures of patient-derived breast cancer explants that neutralizing antibodies and small-molecule inhibitors of hepsin can be used to mitigate the hepsin-induced TGFβ signaling and reduce EGFR protein levels.The study demonstrates a role for hepsin as a regulator of cell proliferation and tumor growth through TGFβ and EGFR pathways, warranting consideration of hepsin as a potential indirect upstream target for therapeutic inhibition of TGFβ and EGFR pathways in cancer.
Project description:Stratification of breast cancers into subtypes are generally based on immune assays on tumor cells and/or mRNA expression of tumor cell enriched tissues. Here, we have laser microdissected tumor epithelium and tumor stroma from 24 breast cancer biopsies (12 luminal-like and 12 basal-like). We hypothesized that the stromal proteome would separate patients with breast into groups independently of the traditional epithelial based subtypes.
Project description:Protein acyltransferase DHHC3 is upregulated in malignant and metastatic human breast cancer, and its elevated expression correlates with diminished survival not only in human breast cancer but also in six other cancer types. In a direct demonstration of pro-tumor DHHC3 function, ZDHHC3 ablation diminished both MDA-MB-231 mammary cell xenografts growth and the size of metastatic lung colonies. Gene array data and fluorescence dye assays documented increased oxidative stress and senescence in ZDHHC3-ablated cells. Consistent with increased senescence, ZDHHC3-ablated tumors showed enhanced recruitment of innate immune cells (anti-tumor macrophages, NK cells) associated with clearance of senescent tumors. ZDHHC3-ablation effects (decreased tumor growth, increased oxidative stress, increased senescence) were reversed upon reconstitution with wildtype, but not enzyme active site-deficient DHHC3. ZDHHC3-ablation effects on oxidative stress/senescence were also substantially reversed upon concomitant ablation of upregulated oxidative stress driver TXNIP. Diminished DHHC3-dependent palmitoylation of ERGIC3 protein likely plays a key role in TXNIP upregulation. In conclusion, through its palmitoylation activity, DHHC3 supports in vivo breast tumor growth by a mechanism involving negative modulation of tumor cell oxidative stress and senescence.
Project description:Development and pre-clinical testing of new cancer therapies is limited by the scarcity of in vivo models that authentically reproduce tumor growth and metastatic progression. We report new models for breast tumor growth and metastasis, in the form of transplantable tumors derived directly from individuals undergoing treatment for breast cancer. These tumor grafts represent the diversity of human breast cancer and maintain essential features of the original tumors, including metastasis to specific sites. Co-engraftment of primary human mesenchymal stem cells maintains phenotypic stability of the grafts and increases tumor growth by promoting angiogenesis. We also report that tumor engraftment is a prognostic indicator of disease outcome for newly diagnosed women; orthotopic breast tumor grafting marks a step toward individualized models for tumor growth, metastasis, and prognosis. This bank of tumor grafts also serves as a publicly available resource for new models in which to study the biology of breast cancer. Single replicates of total RNA from 12 human breast cancer tumors and xenografts of those tumors in immunodeficient mice were hybridized to Agilent Whole Human Genome expression arrays.