Neurofibromin Is an Estrogen Receptor-α Transcriptional Co-repressor in Breast Cancer

Zheng, Zhaoqiang; Anurag, Meenakshi; Lei, Jonathan T.; Cao, Jin; Singh, Purba; Peng, Jiangtao; Kennedy, Hilda; Nguyen, Nancy; Chen, Yue; Lavere, Philip; Li, Jing; Du, Xinhui; Çakar, Burcu; Song, Wei; Kim, Beom-Jun; Shi, Jiejun; Şeker, Sinem; Chan, Doug W.; Chen, Xi; Banks, Kimberly C.; Lanman, Richard B.; Shafaee, Maryam Nemati; Zhang, Xiang H.-F.; Vasaikar, Suhas; Zhang, Bing; Hilsenbeck, Susan G.; Li, Wei; Foulds, Charles E.; Ellis, Matthew J.; Chang, Eric C.

doi:10.1016/j.ccell.2020.02.003

Cited by 67 publications

(77 citation statements)

References 101 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Later genetic analysis revealed that NLS- NF1 transcripts are highly expressed in the tissues in which neurofibromin expression remains high in the adult and which are implicated in NF-1- pathology, that is in neural tissues [ 52 ]. In subsequent studies on the function of the NLS in primary astrocytes and glioblastoma cells [ 18 ], which primarily express NLS transcripts, we provided the mechanism and purpose for a regulated nuclear import of endogenous, full length neurofibromin during the cell cycle: a. at late S phase neurofibromin synthesis increases, and PKCε-phosphorylations on the NLS-adjacent Ser2808 mobilize the molecule to shuttle by the Ran/importin system that requires an NLS into the nucleus (now also confirmed in cancer breast cells [ 53 ]); b. neurofibromin localizes on centrosomes and on the spindle throughout mitosis; and c. siRNA-depletion of all NF1 transcripts leads to errors in chromosome congression. As further established by phospho-ablating or -mimetic constructs of CTD + NLS [ 18 ], only NLS isoforms have the ability to shuttle in and out the nucleus and therefore these congression errors may be attributed mostly to depletion of NLS-neurofibromin.…”

Section: Introductionmentioning

confidence: 99%

Nuclear Isoforms of Neurofibromin Are Required for Proper Spindle Organization and Chromosome Segregation

Peta

Tsirimonaki

Samouil

et al. 2020

Cells

View full text Add to dashboard Cite

Mitotic spindles are highly organized, microtubule (MT)-based, transient structures that serve the fundamental function of unerring chromosome segregation during cell division and thus of genomic stability during tissue morphogenesis and homeostasis. Hence, a multitude of MT-associated proteins (MAPs) regulates the dynamic assembly of MTs in preparation for mitosis. Some tumor suppressors, normally functioning to prevent tumor development, have now emerged as significant MAPs. Among those, neurofibromin, the product of the Neurofibromatosis-1 gene (NF1), a major Ras GTPase activating protein (RasGAP) in neural cells, controls also the critical function of chromosome congression in astrocytic cellular contexts. Cell type- and development-regulated splicings may lead to the inclusion or exclusion of NF1exon51, which bears a nuclear localization sequence (NLS) for nuclear import at G2; yet the functions of the produced NLS and ΔNLS neurofibromin isoforms have not been previously addressed. By using a lentiviral shRNA system, we have generated glioblastoma SF268 cell lines with conditional knockdown of NLS or ΔNLS transcripts. In dissecting the roles of NLS or ΔNLS neurofibromins, we found that NLS-neurofibromin knockdown led to increased density of cytosolic MTs but loss of MT intersections, anastral spindles featuring large hollows and abnormal chromosome positioning, and finally abnormal chromosome segregation and increased micronuclei frequency. Therefore, we propose that NLS neurofibromin isoforms exert prominent mitotic functions.

show abstract

Section: Introductionmentioning

confidence: 99%

Nuclear Isoforms of Neurofibromin Are Required for Proper Spindle Organization and Chromosome Segregation

Peta

Tsirimonaki

Samouil

et al. 2020

Cells

View full text Add to dashboard Cite

show abstract

“…The most striking changes in long-term estrogen-deprived tumors; however, were highly recurrent (up to 42%), outlier expression changes. An analysis of tumors with the most recurrent outlier loss, Nearly all recurrences are more similar transcriptionally to their matched primaries than to other, long-term estrogen deprived tumors-reinforcing the notion that advanced cancers generally retain their core transcriptional programming, even after nearly a decade of dormancy [26][27][28][29] . Furthermore, amplifications and deletions of recurrences are markedly similar to primaries, supporting recent evidence from breast cancer single-cell sequencing that structural variation is likely an early event and many CNAs, even in metachronous therapy-resistant tumors, may be shared by the majority of subclones 32 .…”

Section: Discussionmentioning

confidence: 88%

“…Although drastic clonal remodeling was observed at the DNA-level, few recurrent resistance mechanisms were appreciated. A more recent, large-scale study showed activating ERBB2 mutations, MAPK activation and NF1 loss as mechanisms possibly driving endocrine resistance-with some of these alterations being confirmed in subsequent studies [24][25][26][27] . The majority of this work has notably been performed on metastatic tissues-whether or not some of these changes occur locally as a result of estrogenindependence before distant spread is unknown.…”

mentioning

confidence: 82%

Acquired mutations and transcriptional remodeling in long-term estrogen-deprived locoregional breast cancer recurrences

Priedigkeit

Ding

Horne

et al. 2020

Preprint

View full text Add to dashboard Cite

word count: 200ABSTRACT Endocrine therapy resistance is a hallmark of advanced estrogen receptor (ER) positive breast cancer. In this study, we performed DNA/RNA hybrid-capture sequencing on 12 locoregional recurrences after long-term estrogen-deprivation along with each tumor's matched primary.Despite being up to 7 years removed from the primary lesion, most recurrences harbored similar intrinsic transcriptional and copy number profiles. Only two genes, AKAP9 and KMT2C, were found to have single nucleotide variant (SNV) enrichments in more than one recurrence.Enriched mutations in single cases included SNVs within transcriptional regulators such as ARID1A, TP53, FOXO1, BRD1, NCOA1 and NCOR2 with one local recurrence gaining three PIK3CA mutations. In contrast to DNA-level changes, we discovered recurrent outlier mRNA expression alterations were common-including outlier gains in TP63 (n=5 cases [42%]),FGFR4 (n=3 [25%]) and TERT (n=3 [25%]). Recurrent losses involved ESR1 (n=5 [42%]), RELN (n=5 [42%]), SFRP4 (n=4 [33%]) and FOSB (n=4 [33%]). ESR1-depleted recurrences harbored shared transcriptional remodeling events including upregulation of PROM1 and other basal cancer markers. Taken together, this study defines acquired genomic changes in long-term, estrogen-deprived disease, highlights longitudinal RNA-profiling and identifies a common endocrine-resistant breast cancer subtype with basal-like transcriptional reprogramming.

show abstract

“…Although drastic clonal remodeling was observed at the DNA level, few recurrent resistance mechanisms were appreciated. A more recent, large-scale study showed activating ERBB2 mutations, MAPK activation, and NF1 loss as mechanisms possibly driving endocrine resistance—with some of these alterations being confirmed in subsequent studies [ 24 – 27 ]. The majority of this work has notably been performed on metastatic tissues—whether or not some of these changes occur locally as a result of estrogen independence before distant spread is unknown.…”

Section: Introductionmentioning

confidence: 91%

Acquired mutations and transcriptional remodeling in long-term estrogen-deprived locoregional breast cancer recurrences

et al. 2021

View full text Add to dashboard Cite

Background Endocrine therapy resistance is a hallmark of advanced estrogen receptor (ER)-positive breast cancer. In this study, we aimed to determine acquired genomic changes in endocrine-resistant disease. Methods We performed DNA/RNA hybrid-capture sequencing on 12 locoregional recurrences after long-term estrogen deprivation and identified acquired genomic changes versus each tumor’s matched primary. Results Despite being up to 7 years removed from the primary lesion, most recurrences harbored similar intrinsic transcriptional and copy number profiles. Only two genes, AKAP9 and KMT2C, were found to have single nucleotide variant (SNV) enrichments in more than one recurrence. Enriched mutations in single cases included SNVs within transcriptional regulators such as ARID1A, TP53, FOXO1, BRD1, NCOA1, and NCOR2 with one local recurrence gaining three PIK3CA mutations. In contrast to DNA-level changes, we discovered recurrent outlier mRNA expression alterations were common—including outlier gains in TP63 (n = 5 cases [42%]), NTRK3 (n = 5 [42%]), NTRK2 (n = 4 [33%]), PAX3 (n = 4 [33%]), FGFR4 (n = 3 [25%]), and TERT (n = 3 [25%]). Recurrent losses involved ESR1 (n = 5 [42%]), RELN (n = 5 [42%]), SFRP4 (n = 4 [33%]), and FOSB (n = 4 [33%]). ESR1-depleted recurrences harbored shared transcriptional remodeling events including upregulation of PROM1 and other basal cancer markers. Conclusions Taken together, this study defines acquired genomic changes in long-term, estrogen-deprived disease; highlights the importance of longitudinal RNA profiling; and identifies a common ESR1-depleted endocrine-resistant breast cancer subtype with basal-like transcriptional reprogramming.

show abstract

Neurofibromin Is an Estrogen Receptor-α Transcriptional Co-repressor in Breast Cancer

Abstract: Highlights d NF1 is a GAP-independent estrogen receptor transcription co-repressor d Somatic NF1 loss causes tamoxifen/aromatase inhibitor resistance in ER + breast cancer d A MEK inhibitor plus a SERD is effective in NF1 -ER + PDX and cell line models

Cited by 67 publications

References 101 publications

Nuclear Isoforms of Neurofibromin Are Required for Proper Spindle Organization and Chromosome Segregation

Nuclear Isoforms of Neurofibromin Are Required for Proper Spindle Organization and Chromosome Segregation

Acquired mutations and transcriptional remodeling in long-term estrogen-deprived locoregional breast cancer recurrences

Acquired mutations and transcriptional remodeling in long-term estrogen-deprived locoregional breast cancer recurrences

Contact Info

Product

Resources

About