Biology of aromatase inhibitors: pharmacology/endocrinology within the breast

Area of Science:

• Endocrinology
• Oncology
• Pharmacology

Background:

• Mammary adipose tissue and breast cancers can aromatize androgens to oestrogens, potentially fueling hormone-dependent tumors.
• Aromatase inhibitors are crucial for managing hormone-sensitive breast cancers by reducing oestrogen levels.

Purpose of the Study:

• To evaluate the efficacy of novel aromatase inhibitors (formestane, exemestane, anastrozole, letrozole) on oestrogen biosynthesis and endogenous hormone concentrations within the breast.
• To assess the in situ effects of aromatase inhibitors on breast aromatase activity.

Main Methods:

• In vitro incubations of breast cancer and mammary adipose tissue fibroblasts were used to determine drug efficacy (IC50 values).
• A neoadjuvant treatment protocol in postmenopausal women with breast cancer involved breast biopsies before and after 3 months of aromatase inhibitor treatment.
• Radioisotope tracers ([3H]androstenedione and [14C]oestrone) were infused before biopsies to measure in situ aromatase activity.

Main Results:

• In vitro studies showed potent inhibition of aromatase activity by the drugs, with IC50 values between 1 and 50 nM.
• Paradoxically high aromatase activity was observed in vitro with some tissues from patients treated with type II inhibitors, potentially due to reversible inhibition and enzyme induction.
• In situ studies demonstrated that letrozole profoundly inhibited breast aromatase activity and reduced endogenous oestrogens within the breast.

Conclusions:

• Novel aromatase inhibitors are highly effective in reducing oestrogen biosynthesis both in vitro and in situ within the breast.
• These findings support the use of aromatase inhibitors in managing hormone-dependent breast cancers by decreasing oestrogen levels.
• Understanding the in situ effects is crucial for optimizing breast cancer treatment strategies.