Breast Cancer

, Volume 26, Issue 6, pp 748–757 | Cite as

Tumor microenvironmental growth factors induce long-term estrogen deprivation resistance in breast cancer

  • Kouki Tsuboi
  • Chiyuki Uematsu
  • Yuri Yamaguchi
  • Toshifumi Niwa
  • Shin-ichi HayashiEmail author
Original Article



Hormonal therapy is an effective treatment for luminal-like breast cancer. Aromatase inhibitor (AI) is widely used for estrogen receptor-positive, postmenopausal breast cancers. However, resistance is occurred and becomes a serious clinical concern. In general, progression of cancer strongly depends on tumor microenvironment, which may, therefore, also contribute to the development of AI resistance.


We evaluated tumor microenvironment-derived factors with respect to AI resistance using typical estrogen receptor-positive breast cancer cell lines. We established tumor microenvironment-dependent AI-resistant models and elucidated the underlying mechanisms.


T-47D cells had a higher dependence on microenvironment-derived factors, such as estrogen or growth factors, for survival than MCF-7 cells. We, therefore, evaluated tumor microenvironment growth factors with respect to AI resistance using T-47D cells. We established three resistant cell lines (V1, V2, and V3) that survived estrogen deprivation and growth factor-supplemented conditions. These cell lines were deficient in estrogen receptor α expression and estrogen-dependent growth. Among six representative growth factors, epidermal growth factor was the most influential. In these models, HER2 protein was overexpressed without gene amplification and intracellular phosphorylation pathways were activated compared to parental cell lines. Molecular targeting inhibitors revealed that V1 and V2 primarily rely on the PI3 K pathway for survival, whereas V3 relies on the MAPK pathway.


This study demonstrates the importance of tumor microenvironment-derived factors for the development of AI resistance. These resistant models did not utilize the same resistance mechanism, suggesting that flexible strategies are essential in conquering resistance.


Breast cancer Aromatase inhibitor Hormonal therapy resistance Tumor microenvironment 



This study was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan, a Grant-in-Aid for Cancer Research from the Ministry of Health, Labor and Welfare of Japan, the Program for Promotion of Fundamental Studies in Health Science of the National Institute of Biomedical Innovation (NIBIO), and a grant from the Smoking Research Foundation.

Compliance with ethical standards

Conflict of interest

Shin-ichi Hayashi received research grants from Novartis Pharma K.K, Astra Zeneca K.K, and Eisai K.K.

Supplementary material

12282_2019_978_MOESM1_ESM.docx (15 kb)
Supplementary material 1 (DOCX 14 kb)


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Copyright information

© The Japanese Breast Cancer Society 2019

Authors and Affiliations

  • Kouki Tsuboi
    • 1
  • Chiyuki Uematsu
    • 1
  • Yuri Yamaguchi
    • 2
  • Toshifumi Niwa
    • 1
  • Shin-ichi Hayashi
    • 1
    • 3
    Email author
  1. 1.Department of Molecular and Functional Dynamics and Center for Regulatory Epigenome and DiseasesGraduate Tohoku University School of MedicineSendaiJapan
  2. 2.Research Institute for Clinical OncologySaitama Cancer CenterSaitamaJapan
  3. 3.Department of Molecular and Functional Dynamics, Graduate School of MedicineTohoku UniversitySendaiJapan

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