Blog dedicated to the continuous education in Gynecology and Endocrinology

 

Why does oestrogen-only hormone therapy have such a small impact on breast cancer risk? A Hypothesis.

DGYE-2010-0090[488778]

Eden, John

There seems be irrefutable evidence that oestrogen is involved in the pathogenesis of breast cancer. The disease mostly affects women and the epidemiology of breast cancer relates to reproductive markers such as pregnancy, age at menarche and age of menopause. Most breast cancers elaborate oestrogen receptors (ER) and in such cases endocrine therapies such as tamoxifen and aromatase-inhibitors (AIs) are effective adjuvant treatments. more

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Low-dose vaginal estrogens or vaginal moisturizer in breast cancer survivors with urogenital atrophy: a preliminary study.

Biglia Nicoletta – DGYE-2009-0191 [ID 463734], 10

The study aim is to evaluate the efficacy and safety of two low-dose vaginal estrogen treatments (ET) and of a non hormonal vaginal moisturizer in postmenopausal breast cancer survivors with urogenital atrophy. Eighteen patients receiving estriol cream 0.25mg (n=10) or estradiol tablets 12.5mg (n=8) twice/week for 12 weeks were evaluated and compared with 8 patients treated with polycarbophil-based moisturizer 2.5g twice/week. Severity of vaginal atrophy was assessed using subjective [Vaginal Symptoms Score (VSS), Profile Female Sexual Function (PFSF)] and objective [Vaginal Health Index (VHI), Karyopycnotic Index (KI)] evaluations, while safety by measuring endometrial thickness and serum sex hormones levels. After 4 weeks VSS and VHI were significantly improved by both vaginal ETs, with further improvement after 12 weeks. PFSF improved significantly only in estriol group (p=0.02). Safety measurements did not significantly change. Vaginal moisturizer improved VSS at week 4 (p=0.01), but score returned to pre-treatment values at week 12; no significant modification of VHI, KI, PFSF was recorded. Both low-dose vaginal ET are effective for relieving urogenital atrophy, while non-hormonal moisturizer only provides transient benefit. The increase of serum estrogens levels during treatment with vaginal estrogen at these dosages is minimal.

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The Effects of α-Zearalanol and Estradiol Benzoate on Expression of c-Myc, c-Fos and Epidermal Growth Factor Receptor mRNAs in Breast Tissues Implanted into Nude Mice

Deng, Wenhui, Dai, Shunling; Zhang, Yi; Duan, Jinhong; Wu, Yiyong

Abstract: This study was designed to evaluate the effect of a novel phytoestrogen, α-zearalanol (α-ZAL),and estradiol benzoate (B-E2), on c-myc, c-fos and EGFR expression in normal human breast tissue implanted into nude mice. A xenograft-model, pieces of human normal breast tissue implanted subcutaneously into 9-10-week-old athymic nude mice, was established. The mice were divided into five groups subjected to the following treatments: normal saline (Controls); α-zearalanol (α-ZAL) at 1mg/kg and 5mg/kg; and estradiol benzoate (B-E2) at 1mg/kg and 5mg/kg. Treatment was given every other day, and human breast tissues were removed for experiments after treatment for 30 days. The expression of c-myc, c-fos and EGFR mRNAs were determined by in situ hybridization(ISH). α-ZAL decreased expression of c-myc(p<0.05). 1mg/kg α-ZAL increased EGFR expression (p<0.05) and two dosage of α-ZAL increased c-fos expression (p<0.01) compared with control. While B-E2 significantly increased expression of c-myc, c-fos and EGFR mRNAs expression compared with controls (p<0.01). The extents of the increases in EGFRmRNA expression induced by α-ZAL and in c-fos mRNA by 5mg/kg α-ZAL were lower than those induced by B-E2 (p<0.01). These data suggest that the phytoestrogen α-ZAL may be safer than estrogen on breast.

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TISSUE-SELECTIVE REGULATION OF AROMATASE EXPRESSION BY CALCITRIOL: IMPLICATIONS FOR BREAST CANCER THERAPY.

1) Endocrinology. 2010 Jan;151(1):32-42..

Krishnan AV, Swami S, Peng L, Wang J, Moreno J, Feldman D.

Aromatase, the enzyme that catalyzes estrogen synthesis, is critical for the progression of estrogen receptor-positive breast cancer (BCa) in postmenopausal women. We show that calcitriol, the hormonally active form of vitamin D, regulates the expression of aromatase in a tissue-selective manner. Calcitriol significantly decreased aromatase expression in human BCa cells and adipocytes and caused substantial increases in human osteosarcoma cells (a bone cell model exhibiting osteoblast phenotype in culture) and modest increases in ovarian cancer cells. Calcitriol administration to immunocompromised mice bearing human BCa xenografts decreased aromatase mRNA levels in the tumors and the surrounding mammary adipose tissue but did not alter ovarian aromatase expression. In BCa cells, calcitriol also reduced the levels of prostaglandins (PGs), major stimulators of aromatase transcription, by suppressing the expression of cyclooxygenase-2 (which catalyzes PG synthesis) and increasing that of 15-hydroxyprostaglandin dehydrogenase (which catalyzes PG degradation). The mechanism of aromatase down-regulation by calcitriol in BCa cells is therefore 2-fold: a direct repression of aromatase transcription via promoter II through the vitamin D-response elements identified in this promoter and an indirect suppression by reducing the levels of PGs. Combinations of calcitriol with three different aromatase inhibitors (AIs) caused enhanced inhibition of BCa cell growth. The combination of calcitriol and an AI may have potential benefits for BCa therapy. In addition to augmenting the ability of AIs to inhibit BCa growth, calcitriol acting as a selective aromatase modulator that increases aromatase expression in bone would reduce the estrogen deprivation in bone caused by the AIs, thus ameliorating the AI-induced side effect of osteoporosis.

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BRCA1 REGULATES ACETYLATION AND UBIQUITINATION OF ESTROGEN RECEPTOR-ALPHA.

4) Mol Endocrinol. 2010 Jan;24(1):76-90.

Ma Y, Fan S, Hu C, Meng Q, Fuqua SA, Pestell RG, Tomita YA, Rosen EM.

Inherited mutations of the breast cancer susceptibility gene BRCA1 confer a high risk for breast cancer development. The (300)RXKK and (266)KXK motifs have been identified previously as sites for acetylation of the estrogen receptor-alpha (ER-alpha), and (302)K was also found to be a site for BRCA1-mediated mono-ubiquitination of ER-alpha in vitro. Here we show that ER-alpha proteins with single or double lysine mutations of these motifs (including K303R, a cancer-associated mutant) are resistant to inhibition by BRCA1, even though the mutant ER-alpha proteins retain the ability to bind to BRCA1. We also found that BRCA1 overexpression reduced and knockdown increased the level of acetylated wild-type ER-alpha, without changing the total ER-alpha protein level. Increased acetylation of ER-alpha due to BRCA1 small interfering RNA was dependent upon phosphatidylinositol 3-kinase/Akt signaling and on up-regulation of the coactivator p300. In addition, using an in vitro acetylation assay, we found that in vitro-translated wild-type BRCA1 but not a cancer-associated point mutant (C61G) inhibited p300-mediated acetylation of ER-alpha. Furthermore, BRCA1 overexpression increased the levels of mono-ubiquitinated ER-alpha protein, and a BRCA1 mutant that is defective for ubiquitin ligase activity but retains other BRCA1 functions (I26A) did not ubiquitinate ER-alpha or repress its activity in vivo. Finally, ER-alpha proteins with mutations of the (300)RXKK or (266)KXK motifs showed modest or no BRCA1-induced ubiquitination. We propose a model in which BRCA1 represses ER-alpha activity, in part, by regulating the relative degree of acetylation vs. ubiquitination of ER-alpha.

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