Increased estrogen sulfatase (STS) and 17β-hydroxysteroid dehydrogenase type 1(17β-HSD1) following neoadjuvant aromatase inhibitor therapy in breast cancer patients

Aromatase inhibitors (AIs) are considered the gold standard for endocrine therapy of estrogen receptor (ER) positive postmenopausal breast cancer patients. The therapy may enhance therapeutic response and stabilize disease but resistance and disease progression inevitably occur in the patients. These are considered at least partly due to an emergence of alternative intratumoral estrogen production pathways. Therefore, in this study we evaluated effects of exemestane (EXE) upon the enzymes involved in intratumoral estrogen production including estrogen sulfatase (STS), 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), and estrogen sulfotransferase (EST) and correlated the findings with therapeutic responses including Ki67 labeling index (Ki67). 116 postmenopausal patients with invasive ductal carcinoma, stage II/IIIa, were enrolled in JFMC34-0601 clinical trials between March, 2006 and January, 2008. EXE of 25 mg/day was administered according to the protocol. Pre- and posttreatment specimens of 49 cases were available for this study. Status of STS, EST, 17β-HSD1, ER, progesterone receptor (PgR), human epidermal growth factor receptor type 2 (Her2), and Ki67 in pre- and post-specimens were evaluated. Specimens examined before the therapy demonstrated following features; ER+ (100%), PgR+ (85.7%), and Her2+ (77.6%). After treatment, the number of Ki67, PgR, and ER positive carcinoma cells demonstrated significant decrement in clinical response (CliR) and pathological response (PaR) groups. Significant increment of 17β-HSD1 and STS immunoreactivity was detected in all groups examined except for STS in PaR. EST showed significant increment in nonresponsive groups. Alterations of Ki67 of carcinoma cells before and after therapy were subclassified into three groups according to its degrees. Significant alterations of intratumoral enzymes, especially 17β-HSD1 and STS, were correlated with Ki67 reduction after neoadjuvant EXE therapy. This is the first study demonstrating significant increment of STS and 17β-HSD1 following AI neoadjuvant therapy of postmenopausal ER positive breast carcinoma patients. This increment may represent the compensatory response of breast carcinoma tissues to estrogen depletion.