Steroid Sulfatase and Estrogen Sulfotransferase in Colon Carcinoma: Regulators of Intratumoral Estrogen Concentrations and Potent Prognostic Factors

¹ Departments of ¹Surgery and ²Pathology, Tohoku University School of Medicine; ³Department of Pathology, Tohoku University School of Health Sciences, Sendai, Japan; Departments of ⁴Surgery and ⁵Pathology, Miyagi Cancer Center, Natori, Japan; and ⁶Novartis Institutes for BioMedical Research Basel, Oncology Research, Basel, Switzerland

^* To whom correspondence should be addressed. E-mail: t-suzuki{at}patholo2.med.tohoku.ac.jp.

	Abstract

Previous epidemiologic and in vitro studies have indicated a potential involvement of estrogens in the pathogenesis of human colon carcinoma, but the precise roles of estrogens have remained largely unknown. Therefore, in this study, we first measured intratumoral concentrations of estrogens in 53 colon carcinomas using liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS). Tissue concentrations of total estrogen [estrone (E₁) + estradiol] and E₁ were significantly (2.0- and 2.4-fold, respectively) higher in colon carcinoma tissues than in nonneoplastic colonic mucosa (n = 31), and higher intratumoral concentrations of total estrogen and E₁ were significantly associated with adverse clinical outcome. Intratumoral concentration of total estrogen was significantly associated with the combined status of steroid sulfatase (STS) and estrogen sulfotransferase (EST), but not with that of aromatase. Thus, we subsequently examined the STS/EST status in 328 colon carcinomas using immunohistochemistry. Immunoreactivities for STS and EST were detected in 61% and 44% of the cases, respectively. The -/+ group of the STS/EST status was inversely associated with Dukes' stage, depth of invasion, lymph node metastasis, and distant metastasis and positively correlated with Ki-67 labeling index of the carcinomas. In addition, this -/+ group had significantly longer survival, and a multivariate analysis revealed the STS/EST status as an independent prognostic factor. Results from our present study showed that the STS/EST status of carcinoma tissue determined intratumoral estrogen levels and could be a significant prognostic factor in colon carcinoma, suggesting that estrogens are locally produced mainly through the sulfatase pathway and play important roles in the progression of the disease. [Cancer Res 2009;69(3):OF1–9]

Key Words: Colon Carcinoma, Estrogen, Steroid Sulfatase, Estrogen Sulfotransferase, Prognosis