Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Osteotropism in breast cancer metastasis

ABSTRACT: Breast cancer metastases develop in the bone more frequently than any other site, and are a common cause of morbidity in the form of bone pain, pathological fractures, nerve compression, and life-threatening hypercalcemia. Despite ongoing research efforts, the molecular and cellular mechanisms that regulate breast cancer cell homing to and colonization of the bone as well as resultant pathological bone alteration remain poorly understood. To identify key mediators promoting breast cancer metastasis to bone, we utilized an immunocompetent, syngeneic murine model of breast cancer metastasis employing the mammary tumor cell line NT2.5. Following intracardiac injection of NT2.5 cells in neu-N mice, metastases developed in the bone, liver, and lung, closely mimicking the anatomical distribution of metastases in breast cancer patients. Using an in vivo selection process, we established NT2.5 sub-lines demonstrating an enhanced ability to colonize the bone and liver. Genome-wide cDNA microarray analysis comparing gene expression between parental NT2.5 cells and established sub-lines was performed. Individual samples of RNA from parental NT2.5 cells, early passage (BO3 and LI1) sub-lines, and final passage (BO6 and LI3) sub-lines were compared using GeneChip® Mouse Genome 430 2.0 Arrays

ORGANISM(S): Mus musculus

SUBMITTER: Scott Kominsky

PROVIDER: E-GEOD-47714 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Gene Expression Profiling of Breast Cancer Patients with Brain Metastases Brain metastases confer the worst prognosis of breast cancer as no therapy exists that prevents or eliminates the cancer from spreading to the brain. We developed a new computational modeling method to derive specific downstream signaling pathways that reveal unknown target-disease connections and new mechanisms for specific cancer subtypes. The model enables us to reposition drugs based on available gene expression data of patients. We applied this model to repurpose known or shelved drugs for brain, lung, and bone metastases of breast cancer with the hypothesis that cancer subtypes have their own specific signaling mechanisms. To test the hypothesis, we addressed the specific CSBs for each metastasis that satisfy that (1) CSB proteins are activated by the maximal number of enriched signaling pathways specific to this metastasis, and (2) CSB proteins involve in the most differential expressed coding-genes specific to the specific breast cancer metastasis. The identified signaling networks for the three types of metastases contain 31, 15, and 18 proteins, respectively, and are used to reposition 15, 9, and 2 drug candidates for the brain, lung, and bone metastases of breast cancer. We performed in vitro and in vivo preclinical experiments as well as analysis on patient tumor specimens to evaluate the targets and repositioned drugs. Two known drugs, Sunitinib (FDA approved for renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumor) and Dasatinib (FDA approved for chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia), were shown to prohibit the metastatic colonization in brain. The TMH-52 cohort includes 11 patients who were examined with brain metastasis at the time of breast cancer diagnosis. The other 41 patients were examined with other organ metastasis at the time of breast cancer diagnosis.

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Osteotropism in breast cancer metastasis

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