Automated quantification of extranuclear erα using phosphor-integrated dots for predicting endocrine therapy resistance in hr+/her2− breast cancer

Zhaorong Guo, Hiroshi Tada, Narufumi Kitamura, Yo Hamada, Minoru Miyashita, Narumi Harada-Shoji, Akiko Sato, Yohei Hamanaka, Kouki Tsuboi, Nobuhisa Harada, Mayumi Takano-Kasuya, Hisatake Okada, Yasushi Nakano, Noriaki Ohuchi, Shin Ichi Hayashi, Takanori Ishida, Kohsuke Gonda

Research output: Contribution to journalArticle

Abstract

In addition to genomic signaling, Estrogen receptor alpha (ERα) is associated with cell proliferation and survival through extranuclear signaling contributing to endocrine therapy (ET) resistance. However, the relationship between extranuclear ERα and ET resistance has not been extensively studied. We sought to measure extranuclear ERα expression by immunohistochemistry using phosphor-integrated dots (IHC-PIDs) and to assess its predictive value for ET resistance. After quantitative detection of ERα by IHC-PIDs in vitro, we developed “the nearest-neighbor method” to calculate the extranuclear ERα. Furthermore, tissue sections from 65 patients with HR+/HER2- BC were examined by IHC-PIDs, and the total ERα, nuclear ERα, extranuclear ERα PIDs score, and ratio of extranuclear-to-nuclear ERα (ENR) were measured using the novel method. We demonstrate that quantification of ERα using IHC-PIDs exhibited strong correlations to real-time qRT-PCR (r2 = 0.94) and flow cytometry (r2 = 0.98). High ERα ENR was significantly associated with poor overall survival (p = 0.048) and disease-free survival (DFS) (p = 0.007). Multivariate analysis revealed that the ERα ENR was an independent prognostic factor for DFS [hazard ratio, 3.8; 95% CI, 1.4–11.8; p = 0.006]. Our automated measurement has high accuracy to localize and assess extranuclear ERα. A high ERα ENR in HR+/HER2− BC indicates decreased likelihood of benefiting from ET.

Original languageEnglish
Article number526
JournalCancers
Volume11
Issue number4
DOIs
Publication statusPublished - 2019 Apr

Keywords

  • Breast cancer
  • Endocrine therapy resistance
  • Estrogen receptor α
  • IHC-PIDs
  • Prognostic

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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