Control of estrone sulfatase activity in human breast cancer cells: Effect of tibolone and its metabolites

Abstract

Estradiol is one of the most important factors supporting the growth and evolution of breast cancer; consequently, to block this hormone has been one of the main targets of breast cancer treatment in recent years. The evaluation of estrogens (estrone, estradiol and their sulfates) in the breast tissue of postmenopausal patients with breast cancer indicates high levels, particularly of estrone sulfate, which are 15-25 times higher than in the plasma. Two main pathways are involved in the formation of estrogens: the ‘sulfatase’ pathway which transforms estrone sulfate into estrone, and the ‘aromatase’ pathway which converts androgens into estrogens. Comparative studies in breast cancer tissues show that the sulfatase pathway is 50-500 times more important than the aromatase pathway. Using intact cells and physiological concentrations of estrone sulfate (5x 10-⁹ mol/l), the conversion to estradiol was very intense in the hormone-dependent (T-47D, MCF-7) breast cancer cells, but very little or no estradiol was obtained with the hormone-independent (MDA-MB-231, MDA-MB-436) cells. However, when the latter cells were homogenized, the activity of estrone sulfatase increased markedly. This contradiction in the comparison of the sulfatase activity of the intact cell and the homo-genate of the hormone-independent cells can be explained by the presence of inhibitory factor(s) or the absence of positive factor(s) involved in the enzyme activity, which could be related to the evolution of the cancer to hormone-independence.

Testing different substances, it was proven that pro-megestone (R-5020), danazol, nomogestrol acetate, and anti-estrogens are very active in inhibiting sulfatase activity in hormone-dependent breast cancer cells.

Tibolone (Org OD 14) is a synthetic steroid with weak estrogenic, progestagenic and androgenic properties and is extensively used for the treatment of menopausal complaints. In recent studies using this compound and its metabolites, a very intense inhibitory effect in the transformation of estrone sulfate to estradiol was observed in the hormone-dependent breast cancer cells.

It is concluded that, in addition to the control of aromatase, specific inhibition of estrone sulfatase with anti-sulfatase agents can open new possibilities in breast cancer treatment.

Key Words:

• BREAST CANCER
• ESTRONE SULFATASE
• ESTROGEN