TY - JOUR
T1 - Differential involvement of autophagy and apoptosis in response to chemoendocrine and endocrine therapy in breast cancer
T2 - JBCRG-07TR
AU - Ueno, Takayuki
AU - Masuda, Norikazu
AU - Kamigaki, Shunji
AU - Morimoto, Takashi
AU - Saji, Shigehira
AU - Imoto, Shigeru
AU - Sasano, Hironobu
AU - Toi, Masakazu
N1 - Funding Information:
Conflicts of Interest: Takayuki Ueno has received honoraria from Chugai Pharmaceutical Co., Ltd, Eisai Co., Ltd., Novartis Pharma K.K. Masakazu Toi has received honoraria from Novartis Pharma K.K., MSD K.K., Takeda Pharmaceutical Co., Astra Zeneca K.K., Eisai Co., Ltd., Genomic Health, Inc., Chugai Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Bayer AG, Eli Lilly and Co., Daiichi-Sankyo Co., Ltd. Kyowa Hakko Kirin Co., Ltd., C & C Research Laboratories, Yakult Pharmaceutical Industry Co., Ltd., Sanofi KK, Shimadzu Corporation, and Pfizer Inc.; research funding from Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical co., Ltd., Shimadzu Corporation, Astellas Pharma Inc., AFI Corporation, C & C Research Laboratories, and Japan Breast Cancer Research Group Association; intellectual property: JP 2017-143763 WO2017/131162A, 1 Institution, PCT/JP2016/004374; advisory board meeting: Genomic Health, Inc.; travel support: Genomic Health, Inc. and Eli Lilly and Co.; board of directors: Japan Breast Cancer Research Group Organization, Japan Breast Cancer Research Group Association, Kyoto Breast Cancer Research Network, and Organization for Oncology and Translational Research. Shigehira Saji has received honoraria from Astra Zeneca K.K., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Novartis Pharma K.K. and Pfizer Inc. Norikazu Masuda has received honoraria from Chugai Pharmaceutical Co., Ltd., Astra Zeneca K.K., Eisai Co., Ltd., Takeda Pharmaceutical Co. Ltd., Kyowa Hakko Kirin Co., Ltd., and Pfizer Inc. and funding from Chugai Pharmaceutical Co., Ltd. and Eisai Co., Ltd.; board of directors: Japan Breast Cancer Research Group Association. Hironobu Sasano serves as an advisory board of Eli Lilly, and received honoraria for the lectures from Roche, Eli Lilly and Pfizer Oncology.
Funding Information:
Funding: This research was funded by JSPS KAKENHI Grant Number 15K10067.
Publisher Copyright:
© 2019 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2019/2/2
Y1 - 2019/2/2
N2 - Endocrine therapy is an essential component in the curative treatment of hormone receptor (HR)-positive breast cancer. To improve treatment efficacy, the addition of metronomic chemotherapy has been tested and shown to improve therapeutic effects. To better understand cellular reactions to metronomic chemoendocrine therapy, we studied autophagy-related markers, beclin 1 and LC3, and apoptosis-related markers, TUNEL and M30, in pre-and post-treatment cancer tissues from a multicenter neoadjuvant trial, JBCRG-07, in which oral cyclophosphamide plus letrozole were administered to postmenopausal patients with HR-positive breast cancer. Changes in the levels of markers were compared with those following neoadjuvant endocrine therapy according to clinical response. Apoptosis, in addition to autophagy-related markers, increased following metronomic chemoendocrine therapy and such increases were associated with clinical response. By contrast, following endocrine therapy, the levels of apoptosis-related markers did not increase regardless of clinical response, whereas the levels of autophagy-related markers increased. Furthermore, levels of the apoptosis-related marker, M30, decreased in responders of endocrine therapy, suggesting that the induction of apoptosis by metronomic chemoendocrine therapy was involved in the improved clinical outcome compared with endocrine therapy. In conclusion, metronomic chemoendocrine therapy induced a different cellular reaction from that of endocrine therapy, including the induction of apoptosis, which is likely to contribute to improved efficacy compared with endocrine therapy alone.
AB - Endocrine therapy is an essential component in the curative treatment of hormone receptor (HR)-positive breast cancer. To improve treatment efficacy, the addition of metronomic chemotherapy has been tested and shown to improve therapeutic effects. To better understand cellular reactions to metronomic chemoendocrine therapy, we studied autophagy-related markers, beclin 1 and LC3, and apoptosis-related markers, TUNEL and M30, in pre-and post-treatment cancer tissues from a multicenter neoadjuvant trial, JBCRG-07, in which oral cyclophosphamide plus letrozole were administered to postmenopausal patients with HR-positive breast cancer. Changes in the levels of markers were compared with those following neoadjuvant endocrine therapy according to clinical response. Apoptosis, in addition to autophagy-related markers, increased following metronomic chemoendocrine therapy and such increases were associated with clinical response. By contrast, following endocrine therapy, the levels of apoptosis-related markers did not increase regardless of clinical response, whereas the levels of autophagy-related markers increased. Furthermore, levels of the apoptosis-related marker, M30, decreased in responders of endocrine therapy, suggesting that the induction of apoptosis by metronomic chemoendocrine therapy was involved in the improved clinical outcome compared with endocrine therapy. In conclusion, metronomic chemoendocrine therapy induced a different cellular reaction from that of endocrine therapy, including the induction of apoptosis, which is likely to contribute to improved efficacy compared with endocrine therapy alone.
KW - Apoptosis
KW - Autophagy
KW - Beclin 1
KW - Chemoendocrine therapy
KW - Endocrine therapy
KW - LC3
KW - M30
KW - Metronomic
KW - TUNEL
UR - http://www.scopus.com/inward/record.url?scp=85065122404&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85065122404&partnerID=8YFLogxK
U2 - 10.3390/ijms20040984
DO - 10.3390/ijms20040984
M3 - Article
C2 - 30813476
AN - SCOPUS:85065122404
VL - 20
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
SN - 1422-0067
IS - 4
M1 - 984
ER -