Immunolocalization of thymidylate synthase as a favorable prognostic marker in estrogen receptor-positive breast carcinoma

Kiyoshi Takagi¹, Yasuhiro Miki², Yasuhiro Nakamura², Hisashi Hirakawa³, Yoichiro Kakugawa⁴, Goro Amano⁵, Mika Watanabe⁶, Takanori Ishida⁷, Hironobu Sasano^2,6 and Takashi Suzuki¹

Departments of ¹Pathology and Histotechnology, ²Anatomic Pathology and ⁷Surgical Oncology, Tohoku University Graduate School of Medicine, Sendai, Japan; ³Department of Surgery, Tohoku Kosai Hospital, Sendai, Japan; ⁴Department of Breast Oncology, Miyagi Cancer Center Hospital, Natori, Japan; ⁵Department of Surgery, Nihonkai General Hospital, Sakata, Japan; ⁶Department of Pathology, Tohoku University Hospital, Sendai, Japan

Offprint requests to: Kiyoshi Takagi, PhD. Department of Pathology and Histotechnology, Tohoku University Graduate School of Medicine. 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi-ken, 980-8575 Japan. e-mail: k-takagi@med.tohoku.ac.jp

Summary. Background: Thymidylate synthase (TS) is an enzyme involved in DNA synthesis, and it is a target for 5-fluorouracil. Previous studies have demonstrated that TS is a potent estrogen-induced gene in breast carcinoma cells, suggesting the importance of TS in estrogen-receptor (ER)-positive breast carcinoma. TS immunolocalization has been reported previously, but the clinicopathological significance of TS in ER-positive breast carcinoma still remains unclear. Patients and methods: We immunolocalized TS in 178 breast carcinoma tissues in total, and examined its significance according to the ER-status. Results: TS status was positive in 58% of ER-positive ductal carcinoma in situ (DCIS) cases, and it was significantly associated with the Ki-67 and progesterone receptor (PR). Moreover, in ER-positive DCIS patients who received aromatase inhibitor (AI) before surgery, TS immunoreactivity was significantly decreased after AI treatment. In ER-positive invasive ductal carcinoma (IDC) cases, TS status was significantly associated with PR, and it turned out an independent favorable prognostic factor for recurrence of the patients by multivariate analysis. On the other hand, TS status was positively correlated with pathological T factor in ER-negative IDC cases, and tended to have a worse prognosis for disease-free survival of the patients. Conclusion: These results suggest that TS expression is mainly regulated by estrogen in ER-positive breast carcinoma and is associated with estrogen-mediated proliferation. TS status is a favorable prognostic factor in ER-positive IDC patients, which is different from the ER-negative cases. Histol Histopathol 30, 1223-1232 (2015)

Key words: Breast, Carcinoma, Estrogen, Immunohistochemistry, Prognosis

DOI: 10.14670/HH-11-619