Reprogramming of the ERRα and ERα Target Gene Landscape Triggers Tamoxifen Resistance in Breast Cancer

Thewes, Verena; Simon, Ronald; Schroeter, Petra; Schlotter, Magdalena; Anzeneder, Tobias; Büttner, Reinhard; Beneš, Vladimı́r; Sauter, Guido; Burwinkel, Barbara; Nicholson, Robert Ian; Sinn, Hans‐Peter; Schneeweiß, Andreas; Deuschle, Ulrich; Zapatka, Marc; Heck, Stefanie; Lichter, Peter

doi:10.1158/0008-5472.can-14-0652

Cited by 34 publications

(33 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While the specific activities of the ERRs in cancer certainly extend beyond regulating energy metabolism [43,77,81,106,112,113], the findings summarized herein are in support of the view that the ERRs play a central role in coordinating oncometabolic programs which then fuel cancer cell proliferation, migration, angiogenesis and metastasis (Fig. 1).…”

Section: Discussionsupporting

confidence: 78%

There and back again: The journey of the estrogen-related receptors in the cancer realm

Tam

Giguère

2016

The Journal of Steroid Biochemistry and Molecular Biology

View full text Add to dashboard Cite

Section: Discussionsupporting

confidence: 78%

There and back again: The journey of the estrogen-related receptors in the cancer realm

Tam

Giguère

2016

The Journal of Steroid Biochemistry and Molecular Biology

View full text Add to dashboard Cite

“…The EGF pathway can therefore be an alternative activator for ESR1 signaling in breast cancer and provides a molecular explanation for the endocrine therapy resistance often seen in ER+ERBB2+ breast cancers. Analysis of ESR1 and ESRRA cistromes in tamoxifen-sensitive vs -resistant breast cancer cells showed that despite regulating distinct transcriptional networks, their cistromes are reprogramed in tamoxifen-resistant breast cancer cells toward the regulation of genes functionally relevant to resistance (Thewes et al 2015). These studies show that NR binding profiles can be shifted in a contextdependent manner, resulting in altered transcriptional networks that affect disease progression and outcome.…”

Section: Reprogramming Of Nr Binding and Disease Progressionmentioning

confidence: 88%

“…Although ESRRA is associated with increased recurrence and poor outcome (Thewes et al 2015), ESRRG expression is correlated with ESR1 and ERBB4, which are markers of favorable outcome (Ariazi et al 2002). It has been suggested that ESRRA and ESRRG have opposite roles in the regulation of metabolic reprogramming of breast cancer cells (Deblois & Giguere 2013).…”

Section: Estrogen-related Receptors (Errs)mentioning

confidence: 99%

Emerging functional roles of nuclear receptors in breast cancer

Doan

Graham

2017

Journal of Molecular Endocrinology

View full text Add to dashboard Cite

Nuclear receptors (NRs) have been targets of intensive drug development for decades due to their roles as key regulators of multiple developmental, physiological and disease processes. In breast cancer, expression of the estrogen and progesterone receptor remains clinically important in predicting prognosis and determining therapeutic strategies. More recently, there is growing evidence supporting the involvement of multiple nuclear receptors other than the estrogen and progesterone receptors, in the regulation of various processes important to the initiation and progression of breast cancer. We review new insights into the mechanisms of action of NRs made possible by recent advances in genomic technologies and focus on the emerging functional roles of NRs in breast cancer biology, including their involvement in circadian regulation, metabolic reprogramming and breast cancer migration and metastasis.

show abstract

“…Although it has anti-estrogen activity, TAM is widely used to treat ER-positive breast tumors as an adjuvant therapy for early-stage hormone-sensitive breast cancer or first line therapy for metastatic hormone-sensitive breast cancer, and as many as 30% of patients can be refractory to TAM and acquire resistance to TAM along with the loss of ER-α [6, 22–24]. CK-α is one of the targets of therapeutic strategies because it is a key enzyme in choline metabolism and might contribute to TAM resistance [11, 19].…”

Section: Discussionmentioning

confidence: 99%

Investigation of discriminant metabolites in tamoxifen-resistant and choline kinase-alpha-downregulated breast cancer cells using 1H-nuclear magnetic resonance spectroscopy

et al. 2017

View full text Add to dashboard Cite

Metabolites linked to changes in choline kinase-α (CK-α) expression and drug resistance, which contribute to survival and autophagy mechanisms, are attractive targets for breast cancer therapies. We previously reported that autophagy played a causative role in driving tamoxifen (TAM) resistance of breast cancer cells (BCCs) and was also promoted by CK-α knockdown, resulting in the survival of TAM-resistant BCCs. There is no comparative study yet about the metabolites resulting from BCCs with TAM-resistance and CK-α knockdown. Therefore, the aim of this study was to explore the discriminant metabolic biomarkers responsible for TAM resistance as well as CK-α expression, which might be linked with autophagy through a protective role. A total of 33 intracellular metabolites, including a range of amino acids, energy metabolism-related molecules and others from cell extracts of the parental cells (MCF-7), TAM-resistant cells (MCF-7/TAM) and CK-α knockdown cells (MCF-7/shCK-α, MCF-7/TAM/shCK-α) were analyzed by proton nuclear magnetic resonance spectroscopy (1H-NMRS). Principal component analysis (PCA) and partial least square discriminant analysis (PLS-DA) revealed the existence of differences in the intracellular metabolites to separate the 4 groups: MCF-7 cells, MCF-7/TAM cells, MCF-7-shCK-α cells, and MCF-7/TAM/shCK-α cells. The metabolites with VIP>1 contributed most to the differentiation of the cell groups, and they included fumarate, UA (unknown A), lactate, myo-inositol, glycine, phosphocholine, UE (unknown E), glutamine, formate, and AXP (AMP/ADP/ATP). Our results suggest that these altered metabolites would be promising metabolic biomarkers for a targeted therapeutic strategy in BCCs that exhibit TAM-resistance and aberrant CK-α expression, which triggers a survival and drug resistance mechanism.

show abstract

Reprogramming of the ERRα and ERα Target Gene Landscape Triggers Tamoxifen Resistance in Breast Cancer

Cited by 34 publications

References 48 publications

There and back again: The journey of the estrogen-related receptors in the cancer realm

There and back again: The journey of the estrogen-related receptors in the cancer realm

Emerging functional roles of nuclear receptors in breast cancer

Investigation of discriminant metabolites in tamoxifen-resistant and choline kinase-alpha-downregulated breast cancer cells using 1H-nuclear magnetic resonance spectroscopy

Contact Info

Product

Resources

About