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Open AccessArticle

Automated Quantification of Extranuclear ERα Using Phosphor-Integrated Dots for Predicting Endocrine Therapy Resistance in HR+/HER2 Breast Cancer

1
Department of Breast and Endocrine Surgical Oncology, Graduate School of Medicine, Tohoku University, Sendai, Miyagi 980-8574, Japan
2
Department of Medical Physics, Graduate School of Medicine, Tohoku University, Sendai, Miyagi 980-8574, Japan
3
Department of Molecular and Functional Dynamics, Graduate School of Medicine, Tohoku University, Sendai, Miyagi 980-8574, Japan
4
Bio Systems Development Group, Bio Advanced Technology Division, Corporate R&D Headquarters, KONICA MINOLTA, INC., Hino, Tokyo 191-8511, Japan
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(4), 526; https://doi.org/10.3390/cancers11040526
Received: 2 March 2019 / Revised: 1 April 2019 / Accepted: 9 April 2019 / Published: 12 April 2019
(This article belongs to the Collection Cancer Biomarkers)
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. View Full-Text
Keywords: breast cancer; estrogen receptor α; IHC-PIDs; prognostic; endocrine therapy resistance breast cancer; estrogen receptor α; IHC-PIDs; prognostic; endocrine therapy resistance
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Guo, Z.; Tada, H.; Kitamura, N.; Hamada, Y.; Miyashita, M.; Harada-Shoji, N.; Sato, A.; Hamanaka, Y.; Tsuboi, K.; Harada, N.; Takano-Kasuya, M.; Okada, H.; Nakano, Y.; Ohuchi, N.; Hayashi, S.-I.; Ishida, T.; Gonda, K. Automated Quantification of Extranuclear ERα Using Phosphor-Integrated Dots for Predicting Endocrine Therapy Resistance in HR+/HER2 Breast Cancer. Cancers 2019, 11, 526.

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