A novel somatic mutation of SIN3A detected in breast cancer by whole-exome sequencing enhances cell proliferation through ERα expression

Abstract

Breast cancer is the most frequent tumor in women, and in nearly two-thirds of cases, the tumors express estrogen receptor α (ERα, encoded by ESR1). Here, we performed whole-exome sequencing of 16 breast cancer tissues classified according to ESR1 expression and 12 samples of whole blood, and detected 310 somatic mutations in cancer tissues with high levels of ESR1 expression. Of the somatic mutations validated by a different deep sequencer, a novel nonsense somatic mutation, c.2830 C>T; p.Gln944*, in transcriptional regulator switch-independent 3 family member A (SIN3A) was detected in breast cancer of a patient. Part of the mutant protein localized in the cytoplasm in contrast to the nuclear localization of ERα, and induced a significant increase in ESR1 mRNA. The SIN3A mutation obviously enhanced MCF7 cell proliferation. In tissue sections from the breast cancer patient with the SIN3A c.2830 C>T mutation, cytoplasmic SIN3A localization was detected within the tumor regions where nuclear enlargement was observed. The reduction in SIN3A mRNA correlates with the recurrence of ER-positive breast cancers on Kaplan-Meier plots. These observations reveal that the SIN3A mutation has lost its transcriptional repression function due to its cytoplasmic localization, and that this repression may contribute to the progression of breast cancer.

Differential complex formation via paralogs in the human Sin3 protein interaction network

“…Thus, our findings indicate that SIN3A and SIN3B have distinct nuclear localization signals. Consistently, it has recently been shown that nonsense mutations at residue 949 in SIN3A results in a truncated protein with cytoplasmic localization (40), suggesting that the NLS of SIN3A resides within its C-terminus and is distinct from SIN3B NLS. Additionally, SIN3A, unlike SIN3B_2, did not enrich KPNA2 KPNA3, KPNA4, or KPNB1 (Fig.…”

Differential Complex Formation via Paralogs in the Human Sin3 Protein Interaction Network

“…Interestingly, a region within SIN3A that aligns with the SIN3B NLS does not appear to influence the nuclear localization of SIN3A. A recent report showed that a truncated form of SIN3A mislocalized within the cytoplasm ( 49 ). As this SIN3A variant resulted from a nonsense mutation at residue 944, the C terminus of SIN3A is likely critical for nuclear import.…”

Transcriptional coactivator PGC-1α contributes to decidualization by forming a histone-modifying complex with C/EBPβ and p300

“…Forty-eight hours after siRNA transfection, ESCs were treated with or without cAMP for 4 days. Total RNAs extracted from three samples (control siRNA with no treatment, control siRNA with cAMP treatment, and WT1 siRNA with cAMP treatment) were subjected to RNA-sequence analysis as reported previously ( 4 , 7 , 83 ). mRNA was purified with oligo dT beads (NEBNext Poly(A) mRNA magnet Isolation Module, New England Biolabs).…”