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The objective is to identify gene signatures and biological pathways associated with human epidermal growth factor receptor 2-positive (HER2+) brain metastasis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We combined laser capture microdissection and gene expression microarrays to analyze malignant epithelium from HER2+ breast cancer brain metastases with that from HER2+ nonmetastatic primary tumors. Differential gene expression was performed including gene set enrichment analysis (GSEA) using publicly available breast cancer gene expression data sets.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In a cohort of HER2+ breast cancer brain metastases, we identified a gene expression signature that anti-correlates with overexpression of\n                      <jats:italic>BRCA1.<\/jats:italic>\n                      Sequence analysis of the HER2+ brain metastases revealed no pathogenic mutations of\n                      <jats:italic>BRCA1<\/jats:italic>\n                      , and therefore the aforementioned signature was designated\n                      <jats:italic>BRCA1 Deficient-Like<\/jats:italic>\n                      (\n                      <jats:italic>BD-L<\/jats:italic>\n                      ). Evaluation of an independent cohort of breast cancer metastases demonstrated that\n                      <jats:italic>BD-L<\/jats:italic>\n                      values are significantly higher in brain metastases as compared to other metastatic sites. Although the\n                      <jats:italic>BD-L<\/jats:italic>\n                      signature is present in all subtypes of breast cancer, it is significantly higher in\n                      <jats:italic>BRCA1<\/jats:italic>\n                      mutant primary tumors as compared with sporadic breast tumors. Additionally,\n                      <jats:italic>BD-L<\/jats:italic>\n                      signature values are significantly higher in HER2-\/ER- primary tumors as compared with HER2+\/ER\u2009+\u2009and HER2-\/ER\u2009+\u2009tumors. The\n                      <jats:italic>BD-L<\/jats:italic>\n                      signature correlates with breast cancer cell line pharmacologic response to a combination of poly (ADP-ribose) polymerase (PARP) inhibitor and temozolomide, and the signature outperformed four published gene signatures of\n                      <jats:italic>BRCA1\/2<\/jats:italic>\n                      deficiency.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      A\n                      <jats:italic>BD-L<\/jats:italic>\n                      signature is enriched in HER2+ breast cancer brain metastases without pathogenic\n                      <jats:italic>BRCA1<\/jats:italic>\n                      mutations. Unexpectedly, elevated\n                      <jats:italic>BD-L<\/jats:italic>\n                      values are found in a subset of primary tumors across all breast cancer subtypes. Evaluation of pharmacological sensitivity in breast cancer cell lines representing all breast cancer subtypes suggests the\n                      <jats:italic>BD-L<\/jats:italic>\n                      signature may serve as a biomarker to identify sporadic breast cancer patients who might benefit from a therapeutic combination of PARP inhibitor and temozolomide and may be indicative of a dysfunctional\n                      <jats:italic>BRCA1<\/jats:italic>\n                      -associated pathway.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/bcr3625","type":"journal-article","created":{"date-parts":[[2014,3,14]],"date-time":"2014-03-14T06:01:46Z","timestamp":1394776906000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["A BRCA1deficient-like signature is enriched in breast cancer brain metastases and predicts DNA damage-induced poly (ADP-ribose) polymerase inhibitor sensitivity"],"prefix":"10.1186","volume":"16","author":[{"given":"Ryan P","family":"McMullin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben S","family":"Wittner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanwei","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin R","family":"Denton-Schneider","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Hicks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raj","family":"Singavarapu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon","family":"Moulis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeongeun","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad R","family":"Akbari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven A","family":"Narod","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth D","family":"Aldape","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia S","family":"Steeg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sridhar","family":"Ramaswamy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis C","family":"Sgroi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2014,3,14]]},"reference":[{"key":"3382_CR1","doi-asserted-by":"publisher","first-page":"5278","DOI":"10.1200\/JCO.2008.19.8481","volume":"27","author":"B Leyland-Jones","year":"2009","unstructured":"Leyland-Jones B: Human epidermal growth factor receptor 2-positive breast cancer and central nervous system metastases. 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