Anti-estrogen Resistance in Human Breast Tumors Is Driven by JAG1-NOTCH4-Dependent Cancer Stem Cell Activity

Date

2015-09-01

Author

Simoes, Bruno M.
O'Brien, Ciara S.
Eyre, Rachel
Silva, Andreia
Yu, Ling
Sarmiento-Castro, Aida
Alferez, Denis G.
Spence, Kath
Santiago-Gomez, Angelica
Chemi, Francesca
Acar, Ahmet
Gandhi, Ashu
Howell, Anthony
Brennan, Keith
Ryden, Lisa
Catalano, Stefania
Ando, Sebastiano
Gee, Julia
Ucar, Ahmet
Sims, Andrew H.
Marangoni, Elisabetta
Farnie, Gillian
Landberg, Goeran
Howell, Sacha J.
Clarke, Robert B.

Metadata

Show full item record

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Item Usage Stats

194
views

0
downloads

Breast cancers (BCs) typically express estrogen receptors (ERs) but frequently exhibit de novo or acquired resistance to hormonal therapies. Here, we show that short-term treatment with the anti-estrogens tamoxifen or fulvestrant decrease cell proliferation but increase BC stem cell (BCSC) activity through JAG1-NOTCH4 receptor activation both in patient-derived samples and xenograft (PDX) tumors. In support of this mechanism, we demonstrate that high ALDH1 predicts resistance in women treated with tamoxifen and that a NOTCH4/HES/HEY gene signature predicts for a poor response/prognosis in 2 ER+ patient cohorts. Targeting of NOTCH4 reverses the increase in Notch and BCSC activity induced by anti-estrogens. Importantly, in PDX tumors with acquired tamoxifen resistance, NOTCH4 inhibition reduced BCSC activity. Thus, we establish that BCSC and NOTCH4 activities predict both de novo and acquired tamoxifen resistance and that combining endocrine therapy with targeting JAG1-NOTCH4 overcomes resistance in human breast cancers.

URI

https://hdl.handle.net/11511/89499

Journal

CELL REPORTS

DOI

https://doi.org/10.1016/j.celrep.2015.08.050

Collections

Department of Biology, Article

Suggestions

OpenMETU
Core

Comparison of GST Isoenzyme Expression in Normal and Neoplastic Breast Tissue: Correlation with Clinical and Prognostic Factors OĞUZTÜZÜN, SERPİL; İşcan, Mesude; ÖZHAVZALI, MÜZEYYEN; Sak, Serpil Dizbay (2009-01-01) Glutathione S-transferases in breast tissue play an important role in the susceptibility to the mutagenic effects of chemical carcinogens and in the response of breast tumors to chemotherapy. In this study the immunohistochemical staining characteristics of glutathione S-transferase isoenzymes (alpha, mu, pi, and theta) were investigated in invasive duct carcinomas and in normal breast tissue of 43 patients. The relationships between the expression of the GST isoenzymes and some clinicopathological features...
Investigation of microRNAs on genomic instability regions in breast cancer Selçuklu, Şadan Duygu; Erson Bensan, Ayşe Elif; Department of Biology (2007) Genomic instability is commonly seen in breast cancers. To date, various chromosomal or segmental loss or amplification regions have been detected in primary tumors and cell lines. Hence, an intensive search for potent tumor suppressors or oncogenes located in these regions continues. MicroRNAs (miRNAs) are ~18-24 nt long non-coding RNAs that regulate protein expression either by target mRNA cleavage or translational repression. We hypothesized that miRNAs located in genomic instability regions in breast ca...
Functional importance of CXXC5 in E2-driven cellular proliferation Razizadeh, Negin; Muyan, Mesut; Department of Biology (2019) 17β-estradiol (E2) as the main circulating estrogen hormone has an important role in the regulation of various tissues including mammary tissue. E2 effects target tissue functions by binding to the nuclear receptors, ERα and β. ERs regulate the expression of target genes. Previous studies conducted in our laboratory indicate that one of these estrogen responsive genes is CXXC5 which is regulated by ERα. CXXC5 has a highly conserved zinc-finger CXXC domain, which makes it a member of zinc-finger CXXC domain ...
Estradiol-Estrogen Receptor alpha Mediates the Expression of the CXXC5 Gene through the Estrogen Response Element-Dependent Signaling Pathway Yasar, Pelin; Ayaz, Gamze; Muyan, Mesut (2016-11-25) 17 beta-estradiol (E2), the primary circulating estrogen hormone, mediates physiological and pathophysiological functions of breast tissue mainly through estrogen receptor alpha (ER alpha). Upon binding to E2, ER alpha modulates the expression of target genes involved in the regulation of cellular proliferation primarily through interactions with specific DNA sequences, estrogen response elements (EREs). Our previous microarray results suggested that E2-ER alpha modulates CXXC5 expression. Because of the pr...
Camptothecin Anticancer Drug Loaded Iron Oxide Micro and Nanoparticles: Tuning Targeted and Sustained Release of the Drug in Bioactive Form Gokduman, Kurtulus; Demir, Ayhan Sıtkı (Bentham Science Publishers Ltd., 2013-12-01) Although Camptothecin (CPT) has significant antitumor activity to lung, ovarian, breast, pancreas, and stomach cancers; lactone ring opening causes a reduction in cytotoxic activity and severe side effects in physiological conditions (pH: 7.4, 37 degrees C) due to decreased cell membrane binding, membrane diffusibility, and intrinsic potency against the topoisomerase target. Taken into consideration the targeted delivery advantage of biocompatible magnetic particles, in order to contribute to the removal of...

Citation Formats

B. M. Simoes et al., “Anti-estrogen Resistance in Human Breast Tumors Is Driven by JAG1-NOTCH4-Dependent Cancer Stem Cell Activity,” CELL REPORTS, pp. 1968–1977, 2015, Accessed: 00, 2021. [Online]. Available: https://hdl.handle.net/11511/89499.