Hormonal treatments and the breast : effects on sex steroid receptor expression and proliferation

Abstract

Breast cancer is the most common malignancy among women in the western world. Hormonal treatments for contraception and replacement after menopause have been associated with an increased risk of breast cancer. The basis of risk associated with hormonal therapies may lie in the regulation of cell proliferation.

Normal breast tissue samples from 27 women undergoing reduction mammoplasties were analysed for sex steroid receptor content and proliferation. Women using hormonal contraceptives displayed a higher proliferation rate (p=0.05) expressed as Ki-67/MIB-1 positivity than non-users. Proliferation displayed a strong positive correlation with IGF-I mRNA expression in breast tissue (rs =0.82, p=0.04). During treatment there was a down regulation of ER values.

FNA biopsies were used to assess epithelial proliferation in normal breast tissue from 106 healthy premenopausal women with and without oral contraceptives. OC users had a higher (p=0.03) proliferation rate (mean 4.8 % of KI-67/MIB-1 positive cells) than non-users (mean 2.2 %). Increased proliferation was associated with reduced levels of circulating androgens and free testosterone (rs =- 0.38, p<0.05). There was a positive correlation between serum levels of both native progesterone (rs =0.43, p<0.05) and the progestogen levonorgestrel (rs=0.43, p=0.02).

Surgically postmenopausal cynomolgus macaques were treated for 35 months with either CEE, MPA, CEE/MPA or tamoxifen. Proliferation in breast tissue was associated (p=0.016) with increased expression of p53. Tamoxifen was found to exert estrogen-like action in breast tissue by down-regulation of estrogen receptor expression and increased PRB levels. In the endometrium the lack of p53 expression in response to tamoxifen could be associated with an increased risk of endometrial cancer. Estrogen alone and estrogen in combination with progestogen was found to have different effects on the expression of sex steroid receptor isoforms in breast tissue. During combined CEE/MPA treatment both the ER-beta/ER-alpha and the PRA/PRB ratio had a tendency to be lower as compared to treatment with CEE alone. Suppression of the inhibitory isoforms ER-beta and PRA may relate to increased proliferation during combined estrogen/progestogen treatment.

Ongoing HRT at the time of breast cancer diagnosis was found to influence certain tumor characteristics. Among 322 postmenopausal women with breast cancer 128 were using HRT at diagnosis. In this group the mean tissue concentrations of ER were lower (1.17 fmol/µg DNA) than in non-users (1.70 µg/DNA), p<0.05. Different HRT regimens may have different effects which should be considered in the judgement on hormonal dependency and the clinical decision about endocrine therapy in women with breast cancer.