Models and mechanisms of acquired antihormone resistance in breast cancer: significant clinical progress despite limitations

Sweeney, Elizabeth E.; McDaniel, Russell E.; Maximov, Philipp Y.; Fan, Ping; Jordan, V. Craig

doi:10.1515/hmbci-2011-0004

Cited by 80 publications

(67 citation statements)

References 123 publications

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“…This plasticity is well illustrated by the MCF-7 cell line. There are few ER-positive cell lines (42), but based on results using MCF-7 cells, progress in breast cancer research and patient care has been profound (43). For the first time, we have recapitulated an entirely new MCF-7:PF cell line with both E 2 and SERM-stimulated growth dependent on ER signaling.…”

Section: Discussionmentioning

confidence: 99%

A molecular model for the mechanism of acquired tamoxifen resistance in breast cancer

Fan

Agboke

Cunliffe

et al. 2014

European Journal of Cancer

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Purpose: Estrogen (E2)-stimulated growth re-emerges after a c-Src inhibitor blocking E2-induced apoptosis. A resulting cell line, MCF-7:PF, is selected with features of functional estrogen receptor (ER) and over-expression of insulin-like growth factor-1 receptor beta (IGF-1Rβ). We addressed the question of whether the selective ER modulator (SERM), 4-hydroxytamoxifen (4-OHT) or other SERMs could target ER to prevent E2-stimulated growth in MCF-7:PF cells. Methods: Protein levels of receptors and signaling pathways were examined by immunoblotting. Expression of mRNA was measured through real-time RT-PCR. Recruitment of ER or nuclear receptor coactivator 3 (SRC3) to the promoter of ER-target gene was detected by chromatin-immunoprecipitation (ChIP). Results: 4-OHT and other SERMs stimulated cell growth in an ER-dependent manner. However, unlike E2, 4-OHT suppressed classical ER-target genes as does the pure antiestrogen ICI 182,780 (ICI). ChIP assay indicated that 4-OHT did not recruit ER or SRC3 to the promoter of ER-target gene, pS2. Paradoxically, 4-OHT reduced total IGF-1Rβ but increased phosphorylation of IGF-1Rβ. Mechanistic studies revealed that 4-OHT functioned as an agonist to enhance the non-genomic activity of ER and activate focal adhesion molecules to further increase phosphorylation of IGF-1Rβ. Disruption of membrane-associated signaling, IGF-1R and focal adhesion kinase (FAK), completely abolished 4-OHT-stimulated cell growth. Conclusions: This study is the first to recapitulate a cellular model in vitro of acquired tamoxifen resistance developed in athymic mice in vivo. Importantly, it provides a rationale that membrane-associated pathways may be valuable therapeutic targets for tamoxifen resistant patients in clinic.

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Section: Discussionmentioning

confidence: 99%

A molecular model for the mechanism of acquired tamoxifen resistance in breast cancer

Fan

Agboke

Cunliffe

et al. 2014

European Journal of Cancer

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“…Progress has been made in the early diagnosis and treatment of cancer, and in particular, breast cancer [18][19][20][21][22] . The MCF7 cancer cell line can be used to sensitively detect the response of estrogen [23,24] . We have previously investigated the cytotoxicity and anticancer activities of several aryl phosphonates on MCF7 cells [25] .…”

Section: Introductionmentioning

confidence: 99%

Cytotoxic effects of tamoxifen in breast cancer cells

Hassan¹,

Jassam²,

El‐Hiti³

et al. 2018

JUMD

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Aim: To investigate the cytotoxic effects of tamoxifen on the breast cancer cell line (MCF7). Methods:The cytotoxic effects of tamoxifen on MCF7 cells were investigated using caspase-9 activity and high content screening assays. Apoptosis mechanisms following tamoxifen treatment were also investigated. Results:The most significant cytotoxic effect of tamoxifen in MCF7 cells was a half-maximal inhibitory concentration (IC 50 ) of 4.506 µg/mL. A significant increase in caspase-9 activity was also observed when MCF7 cells were treated with tamoxifen (5 µg/mL). Furthermore, increased cell membrane permeability, cytochrome c level, and nuclear intensity were observed with tamoxifen (100 µg/mL) compared with doxorubicin (20 µg/mL) treatment. However, a noticeable decrease in cell viability and mitochondrial membrane permeability was observed with tamoxifen (100 µg/mL) treatment compared with doxorubicin (20 µg/mL) as a positive control. Conclusion:Tamoxifen showed in vitro cytotoxic effects in MCF7 cells as demonstrated by high-content screening and caspase-9 activity assays. Tamoxifen inhibits estrogen mechanisms, although toxic effect was observed.

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“…During the last 40 years, antihormonal therapy targeting estrogen receptor a (ERa) activity in breast cancer has allowed both an increase in relapse-free survival and a 30% decrease in mortality in the 15 years following treatment initiation (1,2). Long-term adjuvant treatments currently used following tumor surgery consist in blocking estrogen action at the receptor using tamoxifen or fulvestrant/ICI182780 (ICI), or inhibiting estrogen biosynthesis using inhibitors of the cytochrome P450 aromatase (CYP19 aka aromatase).…”

Section: Introductionmentioning

confidence: 99%

“…Despite the success of these endocrine therapies, nearly half of breast cancers are, or will become, resistant to these treatments. Multiple mechanisms have been proposed to explain antiestrogen resistance, such as loss or change of ERa expression, alteration in coregulator expression and/or activity, and aberrant growth factor signaling (2,3). Endocrine resistance results in uncontrolled proliferation and deregulation of the ERa transcriptome, notably in genes involved in cell cycle and apoptosis (3,4).…”

Section: Introductionmentioning

confidence: 99%

LRH-1 Governs Vital Transcriptional Programs in Endocrine-Sensitive and -Resistant Breast Cancer Cells

Bianco

Brunelle²,

Jangal

et al. 2014

Cancer Research

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Tumor characteristics are decisive in the determination of treatment strategy for patients with breast cancer. Patients with estrogen receptor a (ERa)-positive breast cancer can benefit from long-term hormonal treatment. Nonetheless, the majority of patients will develop resistance to these therapies. Here, we investigated the role of the nuclear receptor liver receptor homolog-1 (LRH-1, NR5A2) in antiestrogen-sensitive and -resistant breast cancer cells. We identified genome-wide LRH-1-binding sites using ChIP-seq (chromatin immunoprecipitation sequencing), uncovering preferential binding to regions distal to transcriptional start sites. We further characterized these LRH-1-binding sites by integrating overlapping layers of specific chromatin marks, revealing that many LRH-1-binding sites are active and could be involved in long-range enhancer-promoter looping. Combined with transcriptome analysis of LRH-1-depleted cells, these results show that LRH-1 regulates specific subsets of genes involved in cell proliferation in antiestrogen-sensitive and antiestrogen-resistant breast cancer cells. Furthermore, the LRH-1 transcriptional program is highly associated with a signature of poor outcome and high-grade breast cancer tumors in vivo. Herein, we report the genome-wide location and molecular function of LRH-1 in breast cancer cells and reveal its therapeutic potential for the treatment of breast cancers, notably for tumors resistant to treatments currently used in therapies. Cancer Res; 74(7); 2015-25. Ó2014 AACR.

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Models and mechanisms of acquired antihormone resistance in breast cancer: significant clinical progress despite limitations

Cited by 80 publications

References 123 publications

A molecular model for the mechanism of acquired tamoxifen resistance in breast cancer

A molecular model for the mechanism of acquired tamoxifen resistance in breast cancer

Cytotoxic effects of tamoxifen in breast cancer cells

LRH-1 Governs Vital Transcriptional Programs in Endocrine-Sensitive and -Resistant Breast Cancer Cells

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