Molecular changes associated with the acquisition of oestrogen hypersensitivity in MCF-7 breast cancer cells on long-term oestrogen deprivation

Chan, Christina M.W.; Martin, Lesley-Ann; Johnston, Stephen; Ali, Simak; Dowsett, Mitch

doi:10.1016/s0960-0760(02)00074-2

Cited by 122 publications

(123 citation statements)

References 18 publications

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“…The proliferation profile and time lapse for resistance are in agreement with previous studies (Yue et al, 2003;Martin et al, 2005;Shaw et al, 2006;Sadler et al, 2009). At the latter time point evaluated in this study, MCF7-LTED cells are thought to be in 17bE2-hypersensitive status, which should be acquired at between 3-6 months in 17bE2-deprived culture and precedes acquisition of full 17bE2 independence (Masamura et al, 1995;Santen et al, 2001;Chan et al, 2002;Martin et al, 2003).…”

Section: Resultssupporting

confidence: 90%

“…Following these observations, and as a potential second-line therapeutic strategy, we assessed the effect of ICI 182 780 using late-stage (that is, 18 months) MCF7-LTED cells and their parental MCF7 cells. Notably, MCF7-LTED cells were relatively less sensitive to ICI 182 780 (Figure 6a, including controls of ERa and CDK4 levels, right panels), which further supports the hypothesis of full 17bE2 independence at a late time point, but it is in apparent contradiction with previous evidence (Santen et al, 2001;Chan et al, 2002;Martin et al, 2003). An explanation for this discrepancy may be found in the examination of different time points, as there are possibly dynamic profiles after six months in 17bE2-deprived culture.…”

Section: Mechanistic Insight Into Response To Endocrine Therapiessupporting

confidence: 66%

“…Molecular changes during MCF7-LTED adaptation are consistent with growth signaling pathway cross-talk To generate a breast cancer cell model of acquired resistance to AIs, MCF7 cells were cultured in a medium depleted of 17bE2, as described previously (Katzenellenbogen et al, 1987;Welshons and Jordan, 1987;Masamura et al, 1995;Jeng et al, 1998;Stephen et al, 2001;Chan et al, 2002). After initial quiescence for approximately 60 days, cell cultures adapted at 90 days, defined by a diminished proliferation-dependent response from 17bE2 ( Figure 1a).…”

Section: Resultsmentioning

confidence: 84%

“…This theory implies that, although resistant to estrogen deprivation, these tumors are still dependent on ERa as a major driver of cell biology. The apparent sensitivity of MCF7-LTED cells to further antiestrogenic treatment such as fulvestrant (Santen et al, 2001;Chan et al, 2002;Martin et al, 2003) substantiates this theory, leading to the proposal of clinical trials including these treatments and/or growth factor signaling inhibitors. However, these approaches have shown limited efficacy; in fact, fulvestrant only elicits a response in approximately 7% of ERa-positive tumors that regrow under AI therapy, although its clinical use is justified based on a clinical benefit rate of 32% (Chia et al, 2008).…”

Section: Effect Of 17be2 Through Eramentioning

confidence: 84%

“…Potential second-line therapeutic strategies Previous MCF7-LTED models have shown sensitivity to further antiestrogenic treatment with fulvestrant (ICI 182 780), which acts as a pure antagonist leading to ERa degradation (Santen et al, 2001;Chan et al, 2002;Martin et al, 2003;Dowsett et al, 2005b). Following these observations, and as a potential second-line therapeutic strategy, we assessed the effect of ICI 182 780 using late-stage (that is, 18 months) MCF7-LTED cells and their parental MCF7 cells.…”

Section: Mechanistic Insight Into Response To Endocrine Therapiesmentioning

confidence: 99%

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Biological reprogramming in acquired resistance to endocrine therapy of breast cancer

et al. 2010

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Endocrine therapies targeting the proliferative effect of 17b-estradiol through estrogen receptor a (ERa) are the most effective systemic treatment of ERa-positive breast cancer. However, most breast tumors initially responsive to these therapies develop resistance through molecular mechanisms that are not yet fully understood. The longterm estrogen-deprived (LTED) MCF7 cell model has been proposed to recapitulate acquired resistance to aromatase inhibitors in postmenopausal women. To elucidate this resistance, genomic, transcriptomic and molecular data were integrated into the time course of MCF7-LTED adaptation. Dynamic and widespread genomic changes were observed, including amplification of the ESR1 locus consequently linked to an increase in ERa. Dynamic transcriptomic profiles were also observed that correlated significantly with genomic changes and were predicted to be influenced by transcription factors known to be involved in acquired resistance or cell proliferation (for example, interferon regulatory transcription factor 1 and E2F1, respectively) but, notably, not by canonical ERa transcriptional function. Consistently, at the molecular level, activation of growth factor signaling pathways by EGFR/ERBB/AKT and a switch from phospho-Ser118 (pS118)-to pS167-ERa were observed during MCF7-LTED adaptation. Evaluation of relevant clinical settings identified significant associations between MCF7-LTED and breast tumor transcriptome profiles that characterize ERa-negative status, early response to letrozole and tamoxifen, and recurrence after tamoxifen treatment. In accordance with these profiles, MCF7-LTED cells showed increased sensitivity to inhibition of FGFR-mediated signaling with PD173074. This study provides mechanistic insight into acquired resistance to endocrine therapies of breast cancer and highlights a potential therapeutic strategy.

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Section: Resultssupporting

confidence: 90%

Section: Mechanistic Insight Into Response To Endocrine Therapiessupporting

confidence: 66%

Section: Resultsmentioning

confidence: 84%

Section: Effect Of 17be2 Through Eramentioning

confidence: 84%

Section: Mechanistic Insight Into Response To Endocrine Therapiesmentioning

confidence: 99%

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Biological reprogramming in acquired resistance to endocrine therapy of breast cancer

et al. 2010

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Rational management of endocrine resistance in breast cancer

Hurvitz

Pietras

2008

Cancer

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Endocrine therapy for breast cancer was introduced more than 100 years ago. In the last 30 years, it has been demonstrated that tamoxifen significantly improves outcomes for patients with hormone-responsive breast tumors. Aromatase inhibitors, which suppress the production of estrogen, are recognized today as an KEYWORDS: endocrine therapy, metastatic breast cancer, fulvestrant, endocrine resistance, tamoxifen, aromatase inhibitors.T he influence of ovarian hormones on breast cancer was appreciated first more than 100 years ago, when Beatson demonstrated that inoperable breast tumors regress after oophorectomy. 2 Today, 2 classes of antihormone endocrine agents are considered the standard of care for primary treatment of earlyor late-stage HR1 breast cancer: tamoxifen, which blocks ER activity within tumor cells, and aromatase inhibitors (AIs), such as anastrozole, letrozole, or exemestane, which inhibit the production of estrogen through the aromatase enzyme pathway. Whereas tamoxifen is effective in both premenopausal and postmenopausal women, AIs are indicated only in women who are postmenopausal. In the adjuvant setting, several studies have demonstrated that AIs are tolerated well and offer improved disease-free survival compared with

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Steroid hormone receptors and coregulators in endocrine‐resistant and estrogen‐independent breast cancer cells

Sarvilinna

Eronen

Miettinen

et al. 2005

Intl Journal of Cancer

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Resistance to hormonal therapy is often a problem in the treatment of breast cancer patients. It has been suggested that resistance could be explained by altered nuclear hormone receptor or coregulator levels or inappropriately increased agonist activity of selective estrogen receptor modulator (SERM). To test these hypotheses, we have established novel MCF-7 cell line-derived in vitro models of anti-estrogen-and progestin-resistant and estrogen-independent breast cancer by long-term culture in the presence of toremifene and medroxyprogesterone acetate (MPA) and in the absence of estradiol, respectively. Using cell growth and multiprobe ribonuclease protection assays, the expression of 5 nuclear hormone receptors and 9 coregulators as well as the alterations in the cell proliferation and target gene transcription in response to hormonal treatments were studied. Progesterone receptor (PR) expression was decreased and silencing mediator for retinoid acid and thyroid hormone receptors (SMRT) and amplified in breast cancer-1 (AIB1) expression increased in antiestrogen-resistant cells. Estrogen caused PR and ERb upregulation in all cell lines, but we did not observe increased agonist activity of anti-estrogen measured by regulation of these estrogen target genes. Basal ERa levels and estrogenic growth response were decreased and p300/CBP-associated factor (pCAF) and AIB1 upregulated by estrogen in progestin-resistant cells, but coregulator levels were unchanged. Estrogen-independent cells were still estrogen-responsive and PR, nuclear receptor corepressor (NCoR) and SMRT expression was increased whereas steroid receptor coactivator-1 (SRC-1a) and CBP-related protein p300 (p300) expression decreased. Their growth was inhibited by toremifene, but estradiol was able to abrogate this effect, which might have interesting clinical implications concerning the use of postmenopausal hormone replacement therapy. ' 2005 Wiley-Liss, Inc.

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Molecular changes associated with the acquisition of oestrogen hypersensitivity in MCF-7 breast cancer cells on long-term oestrogen deprivation

Cited by 122 publications

References 18 publications

Biological reprogramming in acquired resistance to endocrine therapy of breast cancer

Biological reprogramming in acquired resistance to endocrine therapy of breast cancer

Rational management of endocrine resistance in breast cancer

Steroid hormone receptors and coregulators in endocrine‐resistant and estrogen‐independent breast cancer cells

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