Yes1 signaling mediates the resistance to Trastuzumab/Lap atinib in breast cancer

Tatsuaki Takeda; Hiromasa Yamamoto; Hirotaka Kanzaki; Ken Suzawa; Takahiro Yoshioka; Shuta Tomida; Xiaojiang Cui; Ramachandran Murali; Kei Namba; Hiroki Sato; Hidejiro Torigoe; Mototsugu Watanabe; Kazuhiko Shien; Junichi Soh; Hiroaki Asano; Kazunori Tsukuda; Yoshihisa Kitamura; Shinichiro Miyoshi; Toshiaki Sendo; Shinichi Toyooka

doi:10.1371/journal.pone.0171356

Yes1 signaling mediates the resistance to Trastuzumab/Lap atinib in breast cancer

Tatsuaki Takeda
, Hiromasa Yamamoto
, Hirotaka Kanzaki
, Ken Suzawa
, Takahiro Yoshioka
, Shuta Tomida
, Xiaojiang Cui
, Ramachandran Murali
, Kei Namba
, Hiroki Sato
, Hidejiro Torigoe
, Mototsugu Watanabe
, Kazuhiko Shien
, Junichi Soh
, Hiroaki Asano
, Kazunori Tsukuda
, Yoshihisa Kitamura
, Shinichiro Miyoshi
, Toshiaki Sendo
, Shinichi Toyooka

Research output: Contribution to journal › Article › peer-review

34 Citations (Scopus)

Abstract

Background Overexpression of human epidermal growth factor receptor 2 (HER2) is observed in approximately 15-23% of breast cancers and these cancers are classified as HER2-positive breast cancer. Trastuzumab is the first-line targeted therapeutic drug for HER2-positive breast cancer and has improved patient overall survival. However, acquired resistance to trastuzumab is still a critical issue in breast cancer treatment. We previously established a trastuzumabresistant breast cancer cell line (named as BT-474-R) from a trastuzumab-sensitive HER2-amplified cell line BT-474. Lapatinib is also a molecular-targeted drug for HER2-positive breast cancer, which acquired the resistance to trastuzumab. Acquired resistance to lapatinib is also an issue to be conquered. Methods We established trastuzumab/lapatinib-dual resistant cell line (named as BT-474-RL2) by additionally treating BT-474-R with lapatinib. We analyzed the mechanisms of resistance to trastuzumab and lapatinib. Besides, we analyzed the effect of the detected resistance mechanism in HER2-positive breast cancer patients. Results Proto-oncogene tyrosine-protein kinase Yes1, which is one of the Src family members, was amplified, overexpressed and activated in BT-474-R and BT-474-RL2. Silencing of Yes1 by siRNA induced both BT-474-R and BT-474-RL2 to restore the sensitivity to trastuzumab and lapatinib. Pharmaceutical inhibition of Yes1 by the Src inhibitor dasatinib was also effective to restore the sensitivity to trastuzumab and lapatinib in the two resistant cell lines. Combination treatment with dasatinib and trastuzumab induced down-regulation of signaling molecules such as HER2 and Akt. Moreover, the combination treatments induced G1-phase cell-cycle arrest and apoptosis. Consistent with cell line data, high expression of Yes1 mRNA was correlated with worse prognosis in patients with HER2-positive breast cancer. Conclusion Yes1 plays an important role in acquired resistance to trastuzumab and lapatinib in HER2-positive breast cancer. Our data suggest that pharmacological inhibition of Yes1 may be an effective strategy to overcome resistance to trastuzumab and lapatinib.

Original language	English
Article number	e0171356
Journal	PloS one
Volume	12
Issue number	2
DOIs	https://doi.org/10.1371/journal.pone.0171356
Publication status	Published - Feb 2017

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

ASJC Scopus subject areas

General

Access to Document

10.1371/journal.pone.0171356

Cite this

Takeda, T., Yamamoto, H., Kanzaki, H., Suzawa, K., Yoshioka, T., Tomida, S., Cui, X., Murali, R., Namba, K., Sato, H., Torigoe, H., Watanabe, M., Shien, K., Soh, J., Asano, H., Tsukuda, K., Kitamura, Y., Miyoshi, S., Sendo, T., & Toyooka, S. (2017). Yes1 signaling mediates the resistance to Trastuzumab/Lap atinib in breast cancer. PloS one, 12(2), Article e0171356. https://doi.org/10.1371/journal.pone.0171356

Takeda, T, Yamamoto, H, Kanzaki, H, Suzawa, K, Yoshioka, T, Tomida, S, Cui, X, Murali, R, Namba, K, Sato, H, Torigoe, H, Watanabe, M, Shien, K, Soh, J, Asano, H, Tsukuda, K, Kitamura, Y, Miyoshi, S, Sendo, T & Toyooka, S 2017, 'Yes1 signaling mediates the resistance to Trastuzumab/Lap atinib in breast cancer', PloS one, vol. 12, no. 2, e0171356. https://doi.org/10.1371/journal.pone.0171356

@article{1b14eac39d3644858404fe5f43532f9f,

title = "Yes1 signaling mediates the resistance to Trastuzumab/Lap atinib in breast cancer",

abstract = "Background Overexpression of human epidermal growth factor receptor 2 (HER2) is observed in approximately 15-23\% of breast cancers and these cancers are classified as HER2-positive breast cancer. Trastuzumab is the first-line targeted therapeutic drug for HER2-positive breast cancer and has improved patient overall survival. However, acquired resistance to trastuzumab is still a critical issue in breast cancer treatment. We previously established a trastuzumabresistant breast cancer cell line (named as BT-474-R) from a trastuzumab-sensitive HER2-amplified cell line BT-474. Lapatinib is also a molecular-targeted drug for HER2-positive breast cancer, which acquired the resistance to trastuzumab. Acquired resistance to lapatinib is also an issue to be conquered. Methods We established trastuzumab/lapatinib-dual resistant cell line (named as BT-474-RL2) by additionally treating BT-474-R with lapatinib. We analyzed the mechanisms of resistance to trastuzumab and lapatinib. Besides, we analyzed the effect of the detected resistance mechanism in HER2-positive breast cancer patients. Results Proto-oncogene tyrosine-protein kinase Yes1, which is one of the Src family members, was amplified, overexpressed and activated in BT-474-R and BT-474-RL2. Silencing of Yes1 by siRNA induced both BT-474-R and BT-474-RL2 to restore the sensitivity to trastuzumab and lapatinib. Pharmaceutical inhibition of Yes1 by the Src inhibitor dasatinib was also effective to restore the sensitivity to trastuzumab and lapatinib in the two resistant cell lines. Combination treatment with dasatinib and trastuzumab induced down-regulation of signaling molecules such as HER2 and Akt. Moreover, the combination treatments induced G1-phase cell-cycle arrest and apoptosis. Consistent with cell line data, high expression of Yes1 mRNA was correlated with worse prognosis in patients with HER2-positive breast cancer. Conclusion Yes1 plays an important role in acquired resistance to trastuzumab and lapatinib in HER2-positive breast cancer. Our data suggest that pharmacological inhibition of Yes1 may be an effective strategy to overcome resistance to trastuzumab and lapatinib.",

author = "Tatsuaki Takeda and Hiromasa Yamamoto and Hirotaka Kanzaki and Ken Suzawa and Takahiro Yoshioka and Shuta Tomida and Xiaojiang Cui and Ramachandran Murali and Kei Namba and Hiroki Sato and Hidejiro Torigoe and Mototsugu Watanabe and Kazuhiko Shien and Junichi Soh and Hiroaki Asano and Kazunori Tsukuda and Yoshihisa Kitamura and Shinichiro Miyoshi and Toshiaki Sendo and Shinichi Toyooka",

note = "Publisher Copyright: {\textcopyright} 2017 Takeda et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",

year = "2017",

month = feb,

doi = "10.1371/journal.pone.0171356",

language = "English",

volume = "12",

journal = "PloS one",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "2",

}

TY - JOUR

T1 - Yes1 signaling mediates the resistance to Trastuzumab/Lap atinib in breast cancer

AU - Takeda, Tatsuaki

AU - Yamamoto, Hiromasa

AU - Kanzaki, Hirotaka

AU - Suzawa, Ken

AU - Yoshioka, Takahiro

AU - Tomida, Shuta

AU - Cui, Xiaojiang

AU - Murali, Ramachandran

AU - Namba, Kei

AU - Sato, Hiroki

AU - Torigoe, Hidejiro

AU - Watanabe, Mototsugu

AU - Shien, Kazuhiko

AU - Soh, Junichi

AU - Asano, Hiroaki

AU - Tsukuda, Kazunori

AU - Kitamura, Yoshihisa

AU - Miyoshi, Shinichiro

AU - Sendo, Toshiaki

AU - Toyooka, Shinichi

N1 - Publisher Copyright: © 2017 Takeda et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2017/2

Y1 - 2017/2

N2 - Background Overexpression of human epidermal growth factor receptor 2 (HER2) is observed in approximately 15-23% of breast cancers and these cancers are classified as HER2-positive breast cancer. Trastuzumab is the first-line targeted therapeutic drug for HER2-positive breast cancer and has improved patient overall survival. However, acquired resistance to trastuzumab is still a critical issue in breast cancer treatment. We previously established a trastuzumabresistant breast cancer cell line (named as BT-474-R) from a trastuzumab-sensitive HER2-amplified cell line BT-474. Lapatinib is also a molecular-targeted drug for HER2-positive breast cancer, which acquired the resistance to trastuzumab. Acquired resistance to lapatinib is also an issue to be conquered. Methods We established trastuzumab/lapatinib-dual resistant cell line (named as BT-474-RL2) by additionally treating BT-474-R with lapatinib. We analyzed the mechanisms of resistance to trastuzumab and lapatinib. Besides, we analyzed the effect of the detected resistance mechanism in HER2-positive breast cancer patients. Results Proto-oncogene tyrosine-protein kinase Yes1, which is one of the Src family members, was amplified, overexpressed and activated in BT-474-R and BT-474-RL2. Silencing of Yes1 by siRNA induced both BT-474-R and BT-474-RL2 to restore the sensitivity to trastuzumab and lapatinib. Pharmaceutical inhibition of Yes1 by the Src inhibitor dasatinib was also effective to restore the sensitivity to trastuzumab and lapatinib in the two resistant cell lines. Combination treatment with dasatinib and trastuzumab induced down-regulation of signaling molecules such as HER2 and Akt. Moreover, the combination treatments induced G1-phase cell-cycle arrest and apoptosis. Consistent with cell line data, high expression of Yes1 mRNA was correlated with worse prognosis in patients with HER2-positive breast cancer. Conclusion Yes1 plays an important role in acquired resistance to trastuzumab and lapatinib in HER2-positive breast cancer. Our data suggest that pharmacological inhibition of Yes1 may be an effective strategy to overcome resistance to trastuzumab and lapatinib.

AB - Background Overexpression of human epidermal growth factor receptor 2 (HER2) is observed in approximately 15-23% of breast cancers and these cancers are classified as HER2-positive breast cancer. Trastuzumab is the first-line targeted therapeutic drug for HER2-positive breast cancer and has improved patient overall survival. However, acquired resistance to trastuzumab is still a critical issue in breast cancer treatment. We previously established a trastuzumabresistant breast cancer cell line (named as BT-474-R) from a trastuzumab-sensitive HER2-amplified cell line BT-474. Lapatinib is also a molecular-targeted drug for HER2-positive breast cancer, which acquired the resistance to trastuzumab. Acquired resistance to lapatinib is also an issue to be conquered. Methods We established trastuzumab/lapatinib-dual resistant cell line (named as BT-474-RL2) by additionally treating BT-474-R with lapatinib. We analyzed the mechanisms of resistance to trastuzumab and lapatinib. Besides, we analyzed the effect of the detected resistance mechanism in HER2-positive breast cancer patients. Results Proto-oncogene tyrosine-protein kinase Yes1, which is one of the Src family members, was amplified, overexpressed and activated in BT-474-R and BT-474-RL2. Silencing of Yes1 by siRNA induced both BT-474-R and BT-474-RL2 to restore the sensitivity to trastuzumab and lapatinib. Pharmaceutical inhibition of Yes1 by the Src inhibitor dasatinib was also effective to restore the sensitivity to trastuzumab and lapatinib in the two resistant cell lines. Combination treatment with dasatinib and trastuzumab induced down-regulation of signaling molecules such as HER2 and Akt. Moreover, the combination treatments induced G1-phase cell-cycle arrest and apoptosis. Consistent with cell line data, high expression of Yes1 mRNA was correlated with worse prognosis in patients with HER2-positive breast cancer. Conclusion Yes1 plays an important role in acquired resistance to trastuzumab and lapatinib in HER2-positive breast cancer. Our data suggest that pharmacological inhibition of Yes1 may be an effective strategy to overcome resistance to trastuzumab and lapatinib.

UR - https://www.scopus.com/pages/publications/85011321109

UR - https://www.scopus.com/pages/publications/85011321109#tab=citedBy

U2 - 10.1371/journal.pone.0171356

DO - 10.1371/journal.pone.0171356

M3 - Article

C2 - 28158234

AN - SCOPUS:85011321109

SN - 1932-6203

VL - 12

JO - PloS one

JF - PloS one

IS - 2

M1 - e0171356

ER -

Yes1 signaling mediates the resistance to Trastuzumab/Lap atinib in breast cancer

Abstract

UN SDGs

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this