Effects of aromatase inhibitors on the pathobiology of the human breast, endometrial and ovarian carcinoma.

Abstract

It is very important to examine the influence of inhibition of in situ estrogen production on the pathobiology of human sex steroid-dependent tumors in order to understand the clinical effects of aromatase inhibitors. We have examined the biological changes before and after aromatase inhibitor treatment in vitro (endometrial and ovarian cancer) and in vivo (breast cancer). First, we analyzed these changes using histoculture of 15 human endometrial cancers and 9 ovarian cancers. Five of the fifteen endometrial cancers and four of the nine ovarian cancers demonstrated decreased [3 H]thymidine uptake or Ki67 labeling index after 14α-hydroxy-4-androstene-3,6,17-trione (NKS01) treatment.In ovarian cancer cases, the responsive cases tended to be associated with higher aromatase and estrogen receptor α (ER) expression compared with the other cases but this was not seen in the endometrial cancer cases. There were no changes in ER and aromatase expression before and after NKS01 treatment in either ovarian or endometrial cancer cases. We then studied the same primary human breast tumors before and after aminoglutethimide (AMG, n=3) and 4-hydroxyandrostenedione (4-OHA, n=3) treatment. Tumor aromatase activity increased in 3 cases and decreased or was unchanged in 3 cases but aromatase immunoreactivity in stroma and adipocytes was unaltered in 5 cases. There were no changes in the ER labeling index before or after treatment. Five of the six cases including the responsive cases tended to be associated with decreased cell proliferation or Ki67 expression and increased apoptosis when examined by the TUNEL method. These results indicate that aromatase inhibitors may exert their effects on human breast and other cancers through Endocrine-Related Cancer (1999) 6 197-204 decreasing proliferation and increasing apoptosis, possibly without altering ER status.

Biological Roles of Estrogen and Progesterone in Human Endometrial Carcinoma - New developments in potential endocrine therapy for endometrial cancer -

“…We previously examined the biological changes in endometrial carcinoma tissues before and after aromatase inhibitor treatment. Five of 15 human endometrial carcinoma demonstrated decreased [ 3 H] thymidine uptake or Ki-67 labeling following aromatase inhibitor treatment [22]. Berstein et al reported similar results [63].…”

“…This positive linkage indicates that local aromatase expression plays a role in tumor progression through the formation of in situ estrogens. In addition, we previously reported that an aromatase inhibitor suppressed the proliferation of endometrial carcinoma cells, which exhibited aromatase activities in vitro [22]. Aromatase is considered a key enzyme in the synthesis of estrogen in endometrial carcinoma as well as breast carcinoma.…”

“…The large multi-center trials all demonstrated that aromatase inhibitors contributed significantly to improved disease-free survival and good tolerability in breast carcinoma patients [4,5]. There remain some controversies as to whether or not aromatase inhibitors are effective in patients with endometrial carcinoma, although intratumoral aromatase activity is more frequently detected in endometrial endometrioid carcinoma than in breast carcinoma [22,63,64]. We previously examined the biological changes in endometrial carcinoma tissues before and after aromatase inhibitor treatment.…”

In situ androgen and estrogen biosynthesis in endometrial cancer: focus on androgen actions and intratumoral production

“…Treatment with anastrozole caused a marked decrement in proliferation as demonstrated by decreased Ki-67 expression. Sasano previously reported similar results using [ 3 H] thymidine uptake or Ki-67 labeling (Sasano et al 1999). Therefore, it is important to clarify the roles, including the possibility of application and indication, of aromatase-inhibitory drugs in hormone-receptor positive or hormone-sensitive endometrial carcinoma in postmenopausal patients.…”

Aromatase expression in low-grade endometrial stromal sarcomas: an immunohistochemical study

“…Aromatase inhibitors are now widely used in treatment of estrogen-dependent breast cancer. 14,23,24 Aromatase inhibitors reduce estrogen levels by inhibiting estrogen synthesis in both tumor tissues and peripheral sites, and as a consequence they inhibit the proliferation of the tumor. Aromatase inhibitors may also influence apoptosis.…”