Naoko Hashimoto Takigami1,2, Shimpei Kuniyoshi1,3, Yasuhiro Miki1, Kentaro Tamaki1,2, Yoshihiko Kamada2, Kano Uehara2, Seiko Tsuchiya2, Shigeharu Terukina2, Erina Iwabuchi1, Ayako Kanai1,4, Minoru Miyashita4, Takanori Ishida4, Nobumitsu Tamaki2, Hironobu Sasano5,6. 1. Department of Pathology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan. 2. Department of Breast Surgical Oncology, Nahanishi Clinic, Naha, Okinawa, Japan. 3. Department of Pathology, Tohoku University Hospital, Sendai, Miyagi, Japan. 4. Department of Breast and Endocrine Surgical Oncology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan. 5. Department of Pathology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan. hsasano@patholo2.med.tohoku.ac.jp. 6. Department of Pathology, Tohoku University Hospital, Sendai, Miyagi, Japan. hsasano@patholo2.med.tohoku.ac.jp.
Abstract
PURPOSE: Diabetes Mellitus (DM) has been one of the well known risk factors of breast cancer (BC) development and also associated with adverse clinical outcomes of BC patients. Glucagon-like peptide-1 (GLP-1) receptor agonists have been used as antidiabetic therapeutic agents and recent epidemiological studies have reported their use to be correlated with increased BC risks. However, biological or pathological details have remained unknown. Therefore, in this study, we examined the status of GLP-1 receptor (GLP-1R) in BC with and without DM and correlated the findings with the clinicopathological factors of the patients to explore the possible involvement of GLP-1 in BC pathology. METHODS: We immunolocalized GLP-1R in cancer and adjacent non-pathological breast tissues in BC patients with DM (125 cases) and without DM (58 cases). We then compared the status of GLP-1R with that of fibroblast growth factor 7 (FGF7) and fibroblast growth factor receptor 2 (FGFR2), Ki-67 labeling index (Ki-67 LI) and disease free survival (DFS) of the patients and also between cancerous and non-pathological breast tissues. RESULTS: GLP-1R immunoreactivity was significantly higher (p = 0.044) in the patients with DM than without in carcinoma tissues. However, this was detected only in invasive carcinoma (p < 0.01) and not in non-invasive carcinoma nor non-pathological mammary glands. FGF7 was significantly correlated with the status of GLP-1R in BC (p = 0.045). In addition, in ER positive BC cases, those with GLP-1R positive status tended to have higher Ki-67 LI of more than 14% (p = 0.070). CONCLUSION: These findings all demonstrated the possible association between GLP-1R status and biological features of BC, especially of invasive BC in DM patients.
PURPOSE: Diabetes Mellitus (DM) has been one of the well known risk factors of breast cancer (BC) development and also associated with adverse clinical outcomes of BC patients. Glucagon-like peptide-1 (GLP-1) receptor agonists have been used as antidiabetic therapeutic agents and recent epidemiological studies have reported their use to be correlated with increased BC risks. However, biological or pathological details have remained unknown. Therefore, in this study, we examined the status of GLP-1 receptor (GLP-1R) in BC with and without DM and correlated the findings with the clinicopathological factors of the patients to explore the possible involvement of GLP-1 in BC pathology. METHODS: We immunolocalized GLP-1R in cancer and adjacent non-pathological breast tissues in BC patients with DM (125 cases) and without DM (58 cases). We then compared the status of GLP-1R with that of fibroblast growth factor 7 (FGF7) and fibroblast growth factor receptor 2 (FGFR2), Ki-67 labeling index (Ki-67 LI) and disease free survival (DFS) of the patients and also between cancerous and non-pathological breast tissues. RESULTS: GLP-1R immunoreactivity was significantly higher (p = 0.044) in the patients with DM than without in carcinoma tissues. However, this was detected only in invasive carcinoma (p < 0.01) and not in non-invasive carcinoma nor non-pathological mammary glands. FGF7 was significantly correlated with the status of GLP-1R in BC (p = 0.045). In addition, in ER positive BC cases, those with GLP-1R positive status tended to have higher Ki-67 LI of more than 14% (p = 0.070). CONCLUSION: These findings all demonstrated the possible association between GLP-1R status and biological features of BC, especially of invasive BC in DM patients.
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