Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 7231 - 7241 |
| Number of pages | 11 |
| Journal | Cancer Research |
| Volume | 76 |
| Issue number | 24 |
| DOIs | |
| Publication status | Published - Dec 15 2016 |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
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Alternative polyadenylation in triple-negative breast tumors allows NRAS and c-JUN to bypass PUMILIO posttranscriptional regulation. / Miles, Wayne O.; Lembo, Antonio; Volorio, Angela; Brachtel, Elena; Tian, Bin; Sgroi, Dennis; Provero, Paolo; Dyson, Nicholas.
In: Cancer Research, Vol. 76, No. 24, 15.12.2016, p. 7231 - 7241.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Alternative polyadenylation in triple-negative breast tumors allows NRAS and c-JUN to bypass PUMILIO posttranscriptional regulation
AU - Miles, Wayne O.
AU - Lembo, Antonio
AU - Volorio, Angela
AU - Brachtel, Elena
AU - Tian, Bin
AU - Sgroi, Dennis
AU - Provero, Paolo
AU - Dyson, Nicholas
PY - 2016/12/15
Y1 - 2016/12/15
N2 - Alternative polyadenylation (APA) is a process that changes the posttranscriptional regulation and translation potential of mRNAs via addition or deletion of 3′ untranslated region (3′ UTR) sequences. To identify posttranscriptional-regulatory events affected by APA in breast tumors, tumor datasets were analyzed for recurrent APA events. Motif mapping of the changed 3′ UTR regions found that APA-mediated removal of Pumilio regulatory elements (PRE) was unusually common. Breast tumor subtype-specific APA profiling identified triple-negative breast tumors as having the highest levels of APA. To determine the frequency of these events, an independent cohort of triple-negative breast tumors and normal breast tissue was analyzed for APA. APA-mediated shortening of NRAS and c-JUN was seen frequently, and this correlated with changes in the expression of downstream targets. mRNA stability and luciferase assays demonstrated APA-dependent alterations in RNA and protein levels of affected candidate genes. Examination of clinical parameters of these tumors found those with APA of NRAS and c-JUN to be smaller and less proliferative, but more invasive than non-APA tumors. RT-PCR profiling identified elevated levels of polyadenylation factor CSTF3 in tumors with APA. Overexpression of CSTF3 was common in triple-negative breast cancer cell lines, and elevated CSTF3 levels were sufficient to induce APA of NRAS and c-JUN. Our results support the hypothesis that PRE-containing mRNAs are disproportionately affected by APA, primarily due to high sequence similarity in the motifs utilized by polyadenylation machinery and the PUM complex.
AB - Alternative polyadenylation (APA) is a process that changes the posttranscriptional regulation and translation potential of mRNAs via addition or deletion of 3′ untranslated region (3′ UTR) sequences. To identify posttranscriptional-regulatory events affected by APA in breast tumors, tumor datasets were analyzed for recurrent APA events. Motif mapping of the changed 3′ UTR regions found that APA-mediated removal of Pumilio regulatory elements (PRE) was unusually common. Breast tumor subtype-specific APA profiling identified triple-negative breast tumors as having the highest levels of APA. To determine the frequency of these events, an independent cohort of triple-negative breast tumors and normal breast tissue was analyzed for APA. APA-mediated shortening of NRAS and c-JUN was seen frequently, and this correlated with changes in the expression of downstream targets. mRNA stability and luciferase assays demonstrated APA-dependent alterations in RNA and protein levels of affected candidate genes. Examination of clinical parameters of these tumors found those with APA of NRAS and c-JUN to be smaller and less proliferative, but more invasive than non-APA tumors. RT-PCR profiling identified elevated levels of polyadenylation factor CSTF3 in tumors with APA. Overexpression of CSTF3 was common in triple-negative breast cancer cell lines, and elevated CSTF3 levels were sufficient to induce APA of NRAS and c-JUN. Our results support the hypothesis that PRE-containing mRNAs are disproportionately affected by APA, primarily due to high sequence similarity in the motifs utilized by polyadenylation machinery and the PUM complex.
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U2 - 10.1158/0008-5472.CAN-16-0844
DO - 10.1158/0008-5472.CAN-16-0844
M3 - Article
VL - 76
SP - 7231
EP - 7241
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0008-5472
IS - 24
ER -