TY - JOUR
T1 - Estrogen signaling in cancer microenvironment and prediction of response to hormonal therapy
AU - Hayashi, Shin ichi
AU - Yamaguchi, Yuri
N1 - Funding Information:
We thank Ms. Yuko Seino, Dr. Mitsuyo Matsumoto for their excellent technical assistance and Drs. Akio Inoue (InfoGenes Co.) Ryoichi Kiyama (Natl. Inst. AIST) Masakazu Toi, Shigehira Saji (Tokyo Metropolitan Komagome Hospital), Hirotaka Iwase (Kumamoto University), Takashi Suzuki, Hironobu Sasano, Nobuo Yaegashi (Tohoku University), Hiroyuki Takei, Masafumi Kurosumi (Saitama Cancer Center), Nobuyuki Yoshida (National Defense Medical College), Nobuhiro Harada (Fujita Health University) for their valuable suggestions and kind cooperation. This study was supported in part by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan for Cancer Research, from the Ministry of Health, Labor and Welfare of Japan for Scientific Research Expenses for Health and Welfare Programs and the Foundation for the Promotion of Cancer Research and for Third-Term Comprehensive Control Research for Cancer.
PY - 2008/4
Y1 - 2008/4
N2 - Estrogen plays an essential role in growth and progression of human breast cancer. Particularly, local estrogen biosynthesis must be important for etiology of this disease. Since estrogen signaling is also activated by the growth factor-mediating phosphorylation signal, breast cancer strongly depends upon local cancer microenvironment. Then, to analyze the estrogen-related cancer microenvironment of individual breast cancer tissues, we established new reporter cell system, which was stably transfected GFP reporter DNA inserted estrogen response element in MCF-7 cells. It enables to analyze ERα-activation activity of stromal cells in individual cancer patients. We found that ERα-activation activity and effect of aromatase inhibitors varied among the individual cases but correlated with histological grade, indicating that the ability of stromal cells in adjacent to cancer cells must be unique and important. Furthermore, these ERα-activation signals in the microenvironment stimulate following intracellular estrogen-signal transduction in cancer cells. Our estrogen-responsive microarray analysis, real-time RT-PCR, and immunohistochemical technique revealed several new target genes which correlate with prognosis of breast cancer and play an important role in cancer development. For example, we found that transcription factor EGR3 was the bona fide target gene for ERα and might involve with invasive property in breast cancer. Furthermore, the expression of another downstream gene HDAC6 significantly correlated with survival of breast cancer patients. In vitro study revealed that the HDAC6 caused the deacetylation of α-tubulin in cytosol and induced cell motility in ERα-positive breast cancer cells. We hope that these approaches could provide not only new clues for elucidation of the mechanisms of estrogen-dependent growth and development of breast cancer, but also clinical benefits to patients by assessment of individual response to hormonal therapy.
AB - Estrogen plays an essential role in growth and progression of human breast cancer. Particularly, local estrogen biosynthesis must be important for etiology of this disease. Since estrogen signaling is also activated by the growth factor-mediating phosphorylation signal, breast cancer strongly depends upon local cancer microenvironment. Then, to analyze the estrogen-related cancer microenvironment of individual breast cancer tissues, we established new reporter cell system, which was stably transfected GFP reporter DNA inserted estrogen response element in MCF-7 cells. It enables to analyze ERα-activation activity of stromal cells in individual cancer patients. We found that ERα-activation activity and effect of aromatase inhibitors varied among the individual cases but correlated with histological grade, indicating that the ability of stromal cells in adjacent to cancer cells must be unique and important. Furthermore, these ERα-activation signals in the microenvironment stimulate following intracellular estrogen-signal transduction in cancer cells. Our estrogen-responsive microarray analysis, real-time RT-PCR, and immunohistochemical technique revealed several new target genes which correlate with prognosis of breast cancer and play an important role in cancer development. For example, we found that transcription factor EGR3 was the bona fide target gene for ERα and might involve with invasive property in breast cancer. Furthermore, the expression of another downstream gene HDAC6 significantly correlated with survival of breast cancer patients. In vitro study revealed that the HDAC6 caused the deacetylation of α-tubulin in cytosol and induced cell motility in ERα-positive breast cancer cells. We hope that these approaches could provide not only new clues for elucidation of the mechanisms of estrogen-dependent growth and development of breast cancer, but also clinical benefits to patients by assessment of individual response to hormonal therapy.
KW - Aromatase
KW - Estrogen
KW - Estrogen receptor
KW - Microarray
KW - Stromal cells
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U2 - 10.1016/j.jsbmb.2008.03.013
DO - 10.1016/j.jsbmb.2008.03.013
M3 - Article
C2 - 18424035
AN - SCOPUS:43849112631
VL - 109
SP - 201
EP - 206
JO - Journal of Steroid Biochemistry
JF - Journal of Steroid Biochemistry
SN - 0960-0760
IS - 3-5
ER -
