Expression of Progesterone and Androgen Receptors in the Breast of Premenopausal Women, Considering Menstrual Phase.

BACKGROUND: Progesterone and androgens are important for normal development and tumorigenesis of the breast. PATIENTS AND METHODS: Breast tissue samples from 49 premenopausal women were obtained. The progesterone receptors (PRA, PRB, PGRMC1 and PGRMC2) and the androgen receptor (AR) were determined in malignant and benign breast tumors and control tissues. RESULTS: The PRB and AR mRNA levels were highest in tumors. PGRMC1 and PGRMC2 mRNA levels were higher in malignant tumors compared to their paired normal tissues. PRA protein showed most immunostaining in benign tumors. PRB immunostaining varied according to menstrual phase. AR immunostaining was highest in the glands of malignant tumors. CONCLUSION: Progesterone and androgen receptors are differently regulated in tumors compared to normal breast tissues. A malignant breast tumor could appear PR-negative if collected in the luteal phase, but positive in the follicular phase. This finding may have clinical implications.

Expression of Estrogen Receptors in Relation to Hormone Levels and the Nottingham Prognostic Index.

BACKGROUND: Estrogen hormones have a large impact on both normal development and tumorigenesis of the breast. MATERIALS AND METHODS: Breast tissue samples from 49 women undergoing surgery were included. The estrogen receptors (ERα and ERß), ERα36 and G-coupled estrogen receptor-1 (GPER) were determined in benign and malignant breast tissue. RESULTS: The ERα36 and ERα mRNA levels were highest in malignant tumors. Stromal ERß immunostaining in benign tumors was higher than in the paired normal tissue. GPER expression was lowest in benign tumors. In the malignant tumors, the Nottingham Prognostic Index (NPI) correlated positively with stromal GPER and the serum testosterone level. The serum insulin-like growth factor-1 (IGF-1) level correlated negatively with GPER mRNA and glandular ERα. CONCLUSION: The expression of ERα36 is stronger in malignant breast tissue. The strong positive correlation between NPI and GPER in malignant breast stroma indicates an important role for GPER in breast cancer prognosis.

Megestrol acetate may stimulate the production of insulin-like growth factor 1 in breast tissues of women with breast cancer.

BACKGROUND: In women with breast cancer who were treated with either continuous tamoxifen alone or sequential tamoxifen followed by megestrol acetate (MA), we demonstrated significant positive associations between the breast tumor estrogen receptor (ER) and an increase in serum sex hormone-binding globulin (SHBG) during tamoxifen treatment. We interpreted this as "ER uniformity" in different tissues, e.g., breast, liver. No other associations with ER were found. In the same study, the breast tumor progesterone receptor (PR) was determined. Our aim was to see if there were any associations between PR and endocrine changes during MA treatment. METHODS: The breast tumor PR before treatment and serum insulin-like growth factor I (∂IGF-1), steroids, steroid-binding proteins, and insulin before and during treatment were measured in 17 postmenopausal women with breast cancer who were treated sequentially with tamoxifen 40 mg/day followed by MA 160 mg/day in alternating 3-month periods. RESULTS: During MA treatment periods, the levels of IGF-1 and insulin increased significantly, whereas the levels of androgens, SHBG, corticosteroid-binding globulin, and cortisol decreased significantly. Significant positive correlations were found between the PR content and increments in ∂IGF-1 but not between PR and any other endocrine change. CONCLUSIONS: PR expression in human liver is very weak, but malignant and normal breast tissues secrete considerable amounts of growth hormone and IGF-1 in vitro and in vivo. This activity is stimulated by progestogens. The association between PR and ∂IGF-1 may therefore reflect a direct PR-mediated action of MA on malignant and normal human breast tissues in vivo.

Hormone replacement therapy after breast cancer: 10 year follow up of the Stockholm randomised trial.

BACKGROUND: The management of hormonal deficiency symptoms in breast cancer survivors is an unsolved problem. While hormone replacement therapy (HRT) may increase the risk of breast cancer in healthy women, its effects on recurrence is unclear. Observational studies have suggested decreased recurrence rates from HRT. The few clinical trials in this field have all been closed preterm. METHODS: The Stockholm trial was started in 1997 and designed to minimise the dose of progestogen in the HRT arm. Disease-free women with a history of breast cancer were randomised to HRT (n=188) or no HRT (n=190). The trial was stopped in 2003 when another Swedish study (HABITS, the Hormonal Replacement After Breast Cancer - Is it Safe?) reported increased recurrence. However the Stockholm material showed no excess risk after 4 years of follow-up. A long term follow-up has now been performed. FINDINGS: After 10.8 years of follow-up, there was no difference in new breast cancer events: 60 in the HRT group versus 48 among controls (hazard ratio (HR)=1.3; 95% confidence interval (CI)=0.9-1.9). Among women on HRT, 11 had local recurrence and 12 distant metastases versus 15 and 12 for the controls. There were 14 contra-lateral breast cancers in the HRT group and four in the control group (HR=3.6; 95% CI=1.2-10.9; p=0.013). No differences in mortality or new primary malignancies were found. INTERPRETATION: The number of new events did not differ significantly between groups, in contrast to previous reports. The increased recurrence in HABITS has been attributed to higher progestogen exposure. As both trials were prematurely closed, data do not allow firm conclusions. Both studies found no increased mortality from breast cancer or other causes from HRT. Current guidelines typically consider HRT contraindicated in breast cancer survivors. Findings suggest that, in some women symptom relief may outweigh the potential risks of HRT.

Associations between serum testosterone levels, cell proliferation and progesterone receptor content in normal and malignant breast tissue in postmenopausal women.

Progestogens and progesterone receptors (PR) may play an important role in increased breast proliferation following combined estrogen/progestogen hormone therapy, while androgens may counteract this effect. In 50 untreated healthy postmenopausal women and 48 untreated postmenopausal breast cancer patients, we measured serum levels of testosterone (T), sex hormone-binding globulin (SHBG), estrone (E(1)) and adrenal androgens; and additionally, in the breast cancer patients, cortisol and corticosteroid-binding globulin and endocrine data related to breast proliferation (assessed using the Ki-67/MIB-1 monoclonal antibody) and PR levels (determined by enzyme immunoassay) in the breast cancer tissue. In the healthy women the percentage of MIB-1(+) cells showed significant negative correlations with serum levels of total T, calculated free T (fT) and the fT/E(1) ratio; while in the breast cancer patients PR content showed significant negative correlations with fT level, the fT/E(1) ratio and the T/SHBG ratio. No other correlations were found in any of the groups. Our findings in healthy women confirm previous reports of an antiproliferative effect of androgens in breast tissue and our finding in breast cancer patients suggests that this antiproliferative effect may be mediated via downregulation of PR.

Digitized assessment of mammographic breast density in patients who received low-dose intrauterine levonorgestrel in continuous combination with oral estradiol valerate: a pilot study.

OBJECTIVE: To perform a pilot study of the effects on the breast by low-dose intrauterine progestogen combined with estrogen. DESIGN: A prospective pilot study. SETTING: University hospital. PATIENT(S): Twenty postmenopausal women without any previous breast disorder. INTERVENTION(S): Women were treated with a low-dose intrauterine system releasing 20 microg/24 hours of levonorgestrel in continuous combination with 2 mg of oral E2 valerate. The effects on mammographic breast density, breast cell proliferation, and hormonal levels were followed for 18 months. MAIN OUTCOME MEASURE(S): Change in mammographic breast density and breast cell proliferation. Correlations with levels of hormones, growth factors, and binding proteins. RESULT(S): Three women showed an apparent increase in density. For the remaining 17 women the changes were only a few percent. Digitized assessment of density showed strong correlations with visual classification scales (rs = 0.96-0.97). There was no increase in proliferation as expressed by the percentage of MIB-1-positive breast cells in fine-needle aspiration biopsies. Increase in breast density displayed a positive correlation with patients age (rs = 0.52) and an inverse relationship with levels of E2 (rs = -0.50) and free T (rs = -0.50). CONCLUSION(S): Low-dose intrauterine administration progestogen may develop into an attractive alternative for hormonal therapy in postmenopausal women as endometrial protection may be achieved at very low systemic levels.

Different methods for the detection of small changes in uptake between single-photon emission computed tomography (SPECT) examinations: 99mTc-sestamibi in chemotherapy for breast tumours.

AIM: This study was undertaken to evaluate different methods for the detection of small changes in uptake between single-photon emission computed tomography (SPECT) examinations in the same individual. No standard exists for making digital evaluations at single-photon examinations. For this purpose, we employed a patient cohort from a previous study assessing the response to neoadjuvant chemotherapy for breast cancer using Tc-hexakis-2-methoxyisobutylisonitrile (Tc-sestamibi). METHODS: The tumour uptake in 29 women with locally advanced breast cancer was examined using Tc-sestamibi and SPECT before neoadjuvant chemotherapy and, on average, 19 days after one chemotherapy cycle. The histology of the finally resected tumour confirmed a therapeutic response. Different assessments of the uptake, various levels of background activity subtraction and different reference tissues for relative activity calculations were used. The tumour uptake and activity of the reference tissues were also related to the administered activity. RESULTS: Different definitions of tumour activity had little influence. Relating the tumour uptake to a large portion of the abdomen, as well as visual evaluation, showed a therapeutic response. Comparison with the administered activity showed that the apparent responses were due to an increased activity of the reference tissues. Referring the tumour uptake to the administered activity truly depicted a therapeutic response. CONCLUSIONS: A critical attitude is necessary when making digital evaluations at SPECT. Digital data may seem more relevant than they really are. Relative comparisons may be unreliable. It may be necessary to develop standardized methods for this purpose.

Menopausal hormone therapy after breast cancer: the Stockholm randomized trial.

In 1997 two independent randomized clinical trials, Hormonal Replacement Therapy After Breast Cancer--Is It Safe? (HABITS; 434 patients) and the Stockholm trial (378 patients), were initiated in Sweden to compare menopausal hormone therapy with no menopausal hormone therapy after diagnosis of early-stage breast cancer. Much of the design of both studies was similar; however, a goal of the Stockholm protocol, not shared with the HABITS trial, was to minimize the use of progestogen combined with estrogen. The HABITS trial was prematurely stopped in December 2003, because, at a median follow-up of 2.1 years, the risk for recurrence of breast cancer among patients receiving menopausal hormone therapy was statistically significantly higher (relative hazard [RH] = 3.3, 95% confidence interval [CI] = 1.5 to 7.4) than among those receiving no treatment. In the Stockholm trial, however, at a median follow-up of 4.1 years, the risk of breast cancer recurrence was not associated with menopausal hormone therapy (RH = 0.82, 95% CI = 0.35 to 1.9). Statistically significant heterogeneity in the rate of recurrence was observed (P = .02; two-sided likelihood-ratio test) between the two studies, indicating that chance may not be the only explanation. Doses of estrogen and progestogen and treatment regimens for menopausal hormone therapy may be associated with the recurrence of breast cancer.