New and translational perspectives of oestrogen deprivation in breast cancer

Dunbier, Anita K.; Martin, Lesley-Ann; Dowsett, Mitch

doi:10.1016/j.mce.2010.12.034

Cited by 8 publications

(9 citation statements)

References 30 publications

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“…However, 50p3 β cells demonstrated minimal growth induction following steroid hormone treatment. Estrogen independence developed 9–12 weeks after initiation of selection in Veh cells (data not shown), consistent with previous reports [6, 20]. The emergence of estrogen independence in 1pE and 50p3 β cells was delayed, developing after 6–7mo of selection and 4–5mo selection, respectively (data not shown).…”

Section: Resultssupporting

confidence: 91%

“…Dose–response curves were generated for E2- or 3 β Adiol-induced proliferation for each cell line to determine whether any of the selection lines had developed hypersensitivity to low concentrations of steroid hormone for growth induction, as previously reported [6, 20]. Minor increases in sensitivity (<1-log decrease in EC 50 ) were observed versus parental MCF-7 cells in all selections except 50pE cells, consistent with their parallel phenotype to parental MCF-7 cells (Supplementary Figure 2).…”

Section: Resultsmentioning

confidence: 99%

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Mechanisms of estrogen-independent breast cancer growth driven by low estrogen concentrations are unique versus complete estrogen deprivation

Sikora

Strumba

Lippman

et al. 2012

Breast Cancer Res Treat

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Despite the success of the aromatase inhibitors (AIs) in treating estrogen receptor positive breast cancer, 15–20 % of patients receiving adjuvant AIs will relapse within 5–10 years of treatment initiation. Long-term estrogen deprivation (LTED) of breast cancer cells in culture mimics AI-induced estrogen depletion to dissect mechanisms of AI resistance. However, we hypothesized that a subset of patients receiving AI therapy may maintain low circulating concentrations of estrogens that influence the development of endocrine resistance. We expanded established LTED models to account for incomplete suppression of estrogen synthesis during AI therapy. MCF-7 cells were grown in medium with charcoal-stripped serum supplemented with defined concentrations of 17β-estradiol (E2) or the estrogenic androgen metabolite 5α-androstane-3β,17β-diol (3βAdiol), an endogenous selective estrogen receptor modulator. Cells were selected in concentrations of E2 or 3βAdiol that induce 10 or 90 percent of maximal proliferation (EC10 and EC90, respectively), or estrogen deprived. Estrogen independence was evaluated during selection by assessing cell growth in the absence or presence of E2 or 3βAdiol. Following >7 months of selection, estrogen independence developed in estrogen-deprived cells and EC10-selected cells. Functional analyses demonstrated that estrogen-deprived and EC10-selected cells developed estrogen independence via unique mechanisms, ERα-independent and dependent, respectively. Estrogen-independent proliferation in EC10-selected cells could be blocked by kinase inhibitors. However, these cells were resistant to kinase inhibition in the presence of low steroid concentrations. These data demonstrate that further understanding of the total estrogen environment in patients on AI therapy who experience recurrence is necessary to effectively treat endocrine-resistant disease.

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Section: Resultssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Mechanisms of estrogen-independent breast cancer growth driven by low estrogen concentrations are unique versus complete estrogen deprivation

Sikora

Strumba

Lippman

et al. 2012

Breast Cancer Res Treat

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“…While oestrogen is a recognized mitogen that usually stimulates mammary cell proliferation and inhibits apoptosis through activation of the oestrogen receptor, 1 both preclinical 38–42 and clinical 41 findings suggest that after long-term oestrogen deprivation, adaptive changes in mammary tumor gene expression profiles render tumors paradoxically susceptible to oestrogen-induced apoptosis. 39,40 While the mechanisms are complex and not completely understood, 42 preclinical studies suggest involvement of the Fas/Fas L extrinsic (receptor-mediated) death regulatory pathway 43 and the intrinsic (mitochondrial) apoptotic pathway, mediated via increased expression of several pro-apoptotic proteins including PUMA (p53-unregulated modulator of apoptosis). 44,45 …”

Section: Discussionmentioning

confidence: 99%

Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women's Health Initiative randomised placebo-controlled trial

Anderson

Chlebowski

Aragaki

et al. 2012

The Lancet Oncology

331

268

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Background In contrast to many observational studies, women in the Women’s Health Initiative (WHI) trial randomised to oestrogen-alone had lower invasive breast cancer incidence than those assigned placebo. Influence of oestrogen use on breast cancer mortality has not been reported. Methods Between 1993 and 1998, the WHI enrolled 10,739 postmenopausal women from 40 US centres into a randomized, double-masked, placebo-controlled trial evaluating oral conjugated equine oestrogen (0·625 mg/d). Women aged 50–79 years with prior hysterectomy, anticipated 3-year survival, and mammography clearance were randomized by a computerized, permuted block algorithm, stratified by age group and centre, to receive oestrogen or matching placebo. The trial was terminated early, in 2004, for an adverse effect on stroke. In extended follow-up through August 2009, we assessed long-term effects of oestrogen use on invasive breast cancer incidence, tumor characteristics, and mortality. Cox regression models were used to estimate intention-to-treat hazard ratios [HRs]. Findings After a median 11.8 (interquartile range [IQR], 9·1 to 12·9) years of follow-up, conjugated equine oestrogen-alone use for a median of 5·9 (IQR, 2·5 to 7·3) years was associated with lower invasive breast cancer incidence compared to placebo (151 vs. 199 breast cancers; annualized rates, 0·27% vs. 0·35%; HR, 0·77; 95% confidence interval [CI], 0·62 to 0·95; P=0·02) with no difference (P=0·76) between intervention-phase (HR, 0·79; 95% CI, 0·61 to 1·02) and post-intervention effects (HR, 0·75; 95% CI: 0·51 to 1·09) ). Potential effect modification by benign breast disease (P=0·01) and family history of breast cancer (P=0·02) was observed. In the oestrogen-alone group fewer women died from breast cancer (6 vs.16 deaths; annualized rates 0·009% vs. 0·024%; HR, 0·37; 95% CI, 0·13 to 0·91; P=0.03) and fewer died from all causes after a breast cancer diagnosis (30 vs. 50 deaths; annualized rates, 0·046% vs. 0·076%; HR, 0·62; 95% CI, 0·39 to 0·9;, P=0·04). Interpretation Women with hysterectomy seeking relief of climacteric symptoms may be given reassurance regarding breast cancer influence of oestrogen use consistent with durations observed in this trial. However, these findings do not support oestrogen use for breast cancer risk reduction since this benefit may not apply to populations at higher risk. Funding US National Heart, Lung and Blood Institute. Wyeth provided study medications.

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“…These apparently paradoxical results are consistent with findings emerging from preclinical studies which have identified complex, time dependent effects of changes in the estrogen environment on the influence of estrogen on mammary tissue. While estrogen commonly stimulates breast cell proliferation and inhibitsapoptosis, under conditions of estrogen deprivation,gene expression profile changes occur such that estrogen then inducesrather than inhibits apoptosis (40, 55, 56). In addition, estrogen deprivation can also result in increased estrogen receptor sensitivity, such thatrelatively low estrogen levels are sufficient to stimulate the estrogen pathway and accelerate mammary tumor growth (57).…”

Section: Potential Mediating Mechanisms Of Action On Hormone Therapy mentioning

confidence: 99%

Menopausal hormone therapy and cancer: Changing clinical observations of target site specificity

Chlebowski

Anderson

2014

Steroids

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Menopausal hormone therapy with estrogen plus progestin or estrogen alone (for women with prior hysterectomy) is still used by millions of women for climacteric symptom management throughout the world. Until 2002, hormone therapy influence on cancer risk and other chronic diseases was determined through observational study reports. Since then, results from the Women's Health Initiative randomized, placebo-controlled hormone therapy trials have substantially changed concepts regarding estrogen plus progestin and estrogen alone influence on the most common cancers in postmenopausal women. In these trials, estrogen plus progestin significantly increased breast cancer incidence and deaths from breast cancer, significantly increased deaths from lung cancer, significantly decreased endometrial cancer, and did not have a clinically significant influence on colorectal cancer. In contrast, estrogen alone use in women with prior hysterectomy significantly reduced breast cancer incidence and deaths from breast cancer without significant influence on colorectal cancer or lung cancer. These complex results are discussed in the context of known potential mediating mechanisms of action involved in interactionwith steroid hormone receptors.

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New and translational perspectives of oestrogen deprivation in breast cancer

Abstract: Please cite this article as: Dunbier, A.K., Martin, L.-A., Dowsett, M., 'New and translational perspectives of oestrogen deprivation in breast cancer', Molecular and Cellular Endocrinology (2010),

Cited by 8 publications

References 30 publications

Mechanisms of estrogen-independent breast cancer growth driven by low estrogen concentrations are unique versus complete estrogen deprivation

Mechanisms of estrogen-independent breast cancer growth driven by low estrogen concentrations are unique versus complete estrogen deprivation

Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women's Health Initiative randomised placebo-controlled trial

Menopausal hormone therapy and cancer: Changing clinical observations of target site specificity

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