Mutant SF3B1 promotes AKT- and NF-κB–driven mammary tumorigenesis
Bo Liu, Zhaoqi Liu, Sisi Chen, Michelle Ki, Caroline Erickson, Jorge S. Reis-Filho, Benjamin H. Durham, Qing Chang, Elisa de Stanchina, Yiwei Sun, Raul Rabadan, Omar Abdel-Wahab, Sarat Chandarlapaty
Bo Liu, Zhaoqi Liu, Sisi Chen, Michelle Ki, Caroline Erickson, Jorge S. Reis-Filho, Benjamin H. Durham, Qing Chang, Elisa de Stanchina, Yiwei Sun, Raul Rabadan, Omar Abdel-Wahab, Sarat Chandarlapaty
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Research Article Oncology

Mutant SF3B1 promotes AKT- and NF-κB–driven mammary tumorigenesis

Abstract

Mutations in the core RNA splicing factor SF3B1 are prevalent in leukemias and uveal melanoma, but hotspot SF3B1 mutations are also seen in epithelial malignancies such as breast cancer. Although hotspot mutations in SF3B1 alter hematopoietic differentiation, whether SF3B1 mutations contribute to epithelial cancer development and progression is unknown. Here, we identify that SF3B1 mutations in mammary epithelial and breast cancer cells induce a recurrent pattern of aberrant splicing leading to activation of AKT and NF-κB, enhanced cell migration, and accelerated tumorigenesis. Transcriptomic analysis of human cancer specimens, MMTV-cre Sf3b1K700E/WT mice, and isogenic mutant cell lines identified hundreds of aberrant 3′ splice sites (3′ss) induced by mutant SF3B1. Consistently between mouse and human tumors, mutant SF3B1 promoted aberrant splicing (dependent on aberrant branchpoints as well as pyrimidines downstream of the cryptic 3′ss) and consequent suppression of PPP2R5A and MAP3K7, critical negative regulators of AKT and NF-κB. Coordinate activation of NF-κB and AKT signaling was observed in the knockin models, leading to accelerated cell migration and tumor development in combination with mutant PIK3CA but also hypersensitizing cells to AKT kinase inhibitors. These data identify hotspot mutations in SF3B1 as an important contributor to breast tumorigenesis and reveal unique vulnerabilities in cancers harboring them.

Authors

Bo Liu, Zhaoqi Liu, Sisi Chen, Michelle Ki, Caroline Erickson, Jorge S. Reis-Filho, Benjamin H. Durham, Qing Chang, Elisa de Stanchina, Yiwei Sun, Raul Rabadan, Omar Abdel-Wahab, Sarat Chandarlapaty

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Figure 1

SF3B1 hotspot mutations are recurrent in breast cancer and are significantly associated with mutations activating PI3K signaling and shortened survival.

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SF3B1 hotspot mutations are recurrent in breast cancer and are signific...
(A) Oncoprint of somatic alterations in SF3B1 and other breast cancer drivers across 5366 patients from the METABRIC (23, 65), MSK-IMPACT (24), and TCGA (22) breast cancer cohorts. ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2. (B) SF3B1 mutation maps showing the counts, amino acid change, position, and evidence of mutational hotspots, based on COSMIC database information. The y axis counts at the bottom of the maps reflect the number of identified mutations in the COSMIC database. (C) Purity normalized variant allele frequency (VAF) of PIK3CA and SF3B1 mutations among 51 double-mutated samples in the MSK-IMPACT cohort. (D) Frequency of somatic mutations in patients from the MSK-IMPACT cohort (n = 94) harboring SF3B1 hotspot mutations. Mutation frequency was calculated for each reported gene in 57 primary samples (x axis) and 45 metastasis samples (y axis). (E) Kaplan-Meier curve of disease-free survival in SF3B1 hotspot mutant (n = 13), SF3B1 WT PIK3CA mutant (n = 672), and SF3B1/PIK3CA double-mutant (n = 30) versus WT (n = 772) ER+ breast cancer patients from METABRIC. P values were derived from log-rank test. See also Supplemental Figure 1.