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HER3 and downstream pathways are involved in colonization of brain metastases from breast cancer.

ABSTRACT: INTRODUCTION: Metastases to the brain from breast cancer have a high mortality, and basal-like breast cancers have a propensity for brain metastases. However, the mechanisms that allow cells to colonize the brain are unclear. METHODS: We used morphology, immunohistochemistry, gene expression and somatic mutation profiling to analyze 39 matched pairs of primary breast cancers and brain metastases, 22 unmatched brain metastases of breast cancer, 11 non-breast brain metastases and 6 autopsy cases of patients with breast cancer metastases to multiple sites, including the brain. RESULTS: Most brain metastases were triple negative and basal-like. The brain metastases over-expressed one or more members of the HER family and in particular HER3 was significantly over-expressed relative to matched primary tumors. Brain metastases from breast and other primary sites, and metastases to multiple organs in the autopsied cases, also contained somatic mutations in EGFR, HRAS, KRAS, NRAS or PIK3CA. This paralleled the frequent activation of AKT and MAPK pathways. In particular, activation of the MAPK pathway was increased in the brain metastases compared to the primary tumors. CONCLUSIONS: Deregulated HER family receptors, particularly HER3, and their downstream pathways are implicated in colonization of brain metastasis. The need for HER family receptors to dimerize for activation suggests that tumors may be susceptible to combinations of anti-HER family inhibitors, and may even be effective in the absence of HER2 amplification (that is, in triple negative/basal cancers). However, the presence of activating mutations in PIK3CA, HRAS, KRAS and NRAS suggests the necessity for also specifically targeting downstream molecules.

SUBMITTER: Da Silva L

PROVIDER: S-EPMC2949633 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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HER3 and downstream pathways are involved in colonization of brain metastases from breast cancer.

Da Silva Leonard L Simpson Peter T PT Smart Chanel E CE Cocciardi Sibylle S Waddell Nic N Lane Annette A Morrison Brian J BJ Vargas Ana Cristina AC Healey Sue S Beesley Jonathan J Pakkiri Pria P Parry Suzanne S Kurniawan Nyoman N Reid Lynne L Keith Patricia P Faria Paulo P Pereira Emilio E Skalova Alena A Bilous Michael M Balleine Rosemary L RL Do Hongdo H Dobrovic Alexander A Fox Stephen S Franco Marcello M Reynolds Brent B Khanna Kum Kum KK Cummings Margaret M Chenevix-Trench Georgia G Lakhani Sunil R SR

Breast cancer research : BCR 20100706 4

<h4>Introduction</h4>Metastases to the brain from breast cancer have a high mortality, and basal-like breast cancers have a propensity for brain metastases. However, the mechanisms that allow cells to colonize the brain are unclear.<h4>Methods</h4>We used morphology, immunohistochemistry, gene expression and somatic mutation profiling to analyze 39 matched pairs of primary breast cancers and brain metastases, 22 unmatched brain metastases of breast cancer, 11 non-breast brain metastases and 6 au ...[more]

PMID: 20604919

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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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HER3 and downstream pathways are involved in colonization of brain metastases from breast cancer.

Publications

HER3 and downstream pathways are involved in colonization of brain metastases from breast cancer.

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