CtIP Silencing as a Novel Mechanism of Tamoxifen Resistance in Breast Cancer

Wu, Minhao; Soler, David Ramos; Abba, Martı́n C.; Nunez, María I.; Baer, Richard; Llombart-Cussac, Antonio; Llombart‐Bosch, Antonio; Aldaz, C. Marcelo

doi:10.1158/1541-7786.mcr-07-0126

Cited by 31 publications

(29 citation statements)

References 48 publications

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“…RBBP8 (also known as CtIP) binds directly to Rb, mediates cell cycle regulation, and helps maintain genomic stability, and loss of RBBP8 incurs tamoxifen resistance and sensitizes breast cancer cells to PARP inhibition in vitro (43)(44)(45)(46). Concordant with the GSEA analysis, BoMs have significant expression loss of RBBP8, with 45% of cases showing a greater than 2-fold decrease in expression.…”

Section: Discussionmentioning

confidence: 74%

Exome-capture RNA sequencing of decade-old breast cancers and matched decalcified bone metastases

Priedigkeit¹,

Watters²,

Lucas³

et al. 2017

JCI Insight

111

100

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Section: Discussionmentioning

confidence: 74%

Exome-capture RNA sequencing of decade-old breast cancers and matched decalcified bone metastases

Priedigkeit¹,

Watters²,

Lucas³

et al. 2017

JCI Insight

111

100

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“…Moreover, mouse CtIP is a tumor suppressor [106]. In humans, CtIP deficiency has been associated with breast cancer and decreased abundance of CtIP mRNA correlates with a poor therapeutic response and lower survival rate [107–109]. The roles of CtIP in removing covalent protein-DNA modifications suggests that therapeutics generating protein-DNA adducts combined with Parp1 inhibitors could be effective in treating breast cancers [108].…”

Section: Discussionmentioning

confidence: 99%

CtIP/Ctp1/Sae2, molecular form fit for function

Andres¹,

Williams²

2017

DNA Repair

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Vertebrate CtIP, and its fission yeast (Ctp1), budding yeast (Sae2) and plant (Com1) orthologs have emerged as key regulatory molecules in cellular responses to DNA double strand breaks (DSBs). By modulating the nucleolytic 5′-3′ resection activity of the Mre11/Rad50/Nbs1 (MRN) DSB repair processing and signaling complex, CtIP/Ctp1/Sae2/Com1 is integral to the channeling of DNA double strand breaks through DSB repair by homologous recombination (HR). Nearly two decades since its discovery, emerging new data are defining the molecular underpinnings for CtIP DSB repair regulatory activities. CtIP homologs are largely intrinsically unstructured proteins comprised of expanded regions of low complexity sequence, rather than defined folded domains typical of DNA damage metabolizing enzymes and nucleases. A compact structurally conserved N-terminus forms a functionally critical tetrameric helical dimer of dimers (THDD) region that bridges CtIP oligomers, and is flexibly appended to a conserved C-terminal Sae2-homology DNA binding and DSB repair pathway choice regulatory hub which influences nucleolytic activities of the MRN core nuclease complex. The emerging evidence from structural, biophysical, and biological studies converges on CtIP having functional roles in DSB repair that include: 1) dynamic DNA strand coordination through direct DNA binding and DNA bridging activities, 2) MRN nuclease complex cofactor functions that direct MRN endonucleolytic cleavage of protein-blocked DSB ends and 3) acting as a protein binding hub targeted by the cell cycle regulatory apparatus, which influences CtIP expression and activity via layers of post-translational modifications, protein-protein interactions and DNA binding.

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“…Tamoxifen-sensitive, but not tamoxifen-insensitive, cell lines show immunoreactivity to the H222 antibody (Naundorf et al 2000) and, interestingly, no differences in the ER nucleotide sequences of the ER LBD in tamoxifen-sensitive and -insensitive cell lines were observed. This suggests that either sequences removed from the LBD or other biomacromolecules, such as AEBS or perhaps CtIP (Wu et al 2007), may impart tamoxifen sensitivity directly or indirectly. This notion is further supported by the observation that ER mutations occur at a low frequency in breast cancer patients and do not account for most tamoxifen-resistant breast tumors (Karnik et al 1994, Naundorf et al 2000.…”

Section: Biochemical History Of the Dual Agonist/ Antagonist Activitymentioning

confidence: 99%

Implications of the binding of tamoxifen to the coactivator recognition site of the estrogen receptor

Kojetin¹,

Burris²,

Jensen³

et al. 2008

Endocrine Related Cancer

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A number of studies have reported on the unusual pharmacological behavior of type I antiestrogens, such as tamoxifen. These agents display mixed agonist/antagonist activity in a dose-, cell-, and tissue-specific manner. Consequently, many efforts have been made to develop so-called 'pure' antiestrogens that lack mixed agonist/antagonist activity. The recent report of the structure of estrogen receptor (ER) b with a second molecule of 4-hydroxytamoxifen (HT) bound in the coactivator-binding surface of the ligand-binding domain (LBD) represents the first direct example of a second ER ligand-binding site and provides insight into the possible origin of mixed agonist/antagonist activity of type I antiestrogens. In this review, we summarize the biological reports leading up to the structural conformation of a second ER ligand-binding site, compare the ERb LBD structure bound with two HT molecules to other ER structures, and discuss the potential for small molecular inhibitors designed to directly inhibit ER-coactivator and, more generally, nuclear receptor (NR)-coactivator interactions. The studies support a departure from the traditional paradigm of drug targeting to the ligand-binding site, to that of a rational approach targeting a functionally important surface, namely the NR coactivator-binding (activation function-2) surface. Furthermore, we provide evidence supporting a reevaluation of the strict interpretation of the agonist/antagonist state with respect to the position of helix 12 in the NR LBD.

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CtIP Silencing as a Novel Mechanism of Tamoxifen Resistance in Breast Cancer

Cited by 31 publications

References 48 publications

Exome-capture RNA sequencing of decade-old breast cancers and matched decalcified bone metastases

Exome-capture RNA sequencing of decade-old breast cancers and matched decalcified bone metastases

CtIP/Ctp1/Sae2, molecular form fit for function

Implications of the binding of tamoxifen to the coactivator recognition site of the estrogen receptor

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