Nuclear expression of the RNA-binding protein RBM3 is associated with an improved clinical outcome in breast cancer

Abstract

Single-strand RNA-binding proteins (RBPs) are involved in many aspects of RNA metabolism and in the regulation of gene transcription. The RBP RBM3 was recently suggested to be a proto-oncogene in colorectal cancer; however, such a role has not been corroborated by previous studies in the colon or other tumor types, and the prognostic implications of tumor-specific RBM3 expression remain unclear. Mono-specific antibodies against RBM3 were generated. Antibody specificity was confirmed using siRNA gene silencing, western blotting and immunohistochemistry on a panel of breast cancer cell lines. Using tissue microarrays and IHC, RBM3 protein expression was examined in 48 normal tissues and in 20 common cancers. Additional analysis in two independent breast cancer cohorts (n ¼ 1016) with long-term follow-up was also carried out. RBM3 was upregulated in cancer compared to normal tissues. The nuclear expression of RBM3 in breast cancer was associated with low grade (Po0.001), small tumors (Po0.001), estrogen receptor (ER) positivity (Po0.001) and Ki-67 negativity (Po0.001) in both the breast cancer cohorts. An increased nuclear expression of RBM3 was associated with a prolonged overall and recurrence-free survival. The prognostic value was particularly pronounced in hormone receptor-positive tumors and remained significant in multivariate interaction analysis after controlling for tamoxifen treatment (HR: 0.49, 95% CI: 0.30-0.79, P ¼ 0.004). These data strongly indicate that nuclear RBM3 is an independent favorable prognostic factor in breast cancer, and seems to have a specific role in ER-positive tumors.

Podocalyxin-like and RNA-binding motif protein 3 are prognostic biomarkers in urothelial bladder cancer: a validatory study

“…Herein, a significantly decreased 5-year OS was demonstrated for patients with tumours displaying low expression of RBM3, which is well in line with previous findings in UBC [26], as well as breast cancer [17], epithelial ovarian cancer [18, 30], prostate cancer [19, 21], testicular cancer [25], oesophageal and gastric cancer [23] and melanoma [24]. …”

“…RNA-binding motif protein 3 (RBM3) is an RNA and DNA binding protein that has previously been shown to be upregulated in cancer tissues compared with normal tissue [16], but to be associated with favourable prognosis in several major cancer forms such as breast, ovarian, prostate, testicular, esophageal, colorectal cancer and malignant melanoma [17–25]. In a previous study, we examined the prognostic value of RBM3 expression in a large group of patients with UBC ( n  = 343), and found reduced expression to be associated with clinically more aggressive tumours and an independent factor of poor prognosis in the cohort as a whole, as well as in the Ta/T1 group [26].…”

Dissecting the expression landscape of RNA-binding proteins in human cancers

“…RBM3 has seldom been found expressed in normal tissues, but it is more expressed in common cancers, particularly for the nuclear expression of Estrogen-Receptor (ER) positive tumors. These findings suggest the possible utility of the gene as a positive prognostic marker [47,48]. …”

Stress-Response Protein RBM3 Attenuates the Stem-like Properties of Prostate Cancer Cells by Interfering with CD44 Variant Splicing

“…For example, while RBM3 is thought to be a proto-oncogene that is upregulated in many cancers where it appears to protect cancer cells from mitotic catastrophe (19) or apoptosis (33), several studies also show that high RBM3 expression in cancer cells, especially in the nucleus, predicts a better prognosis in a variety of cancers, including prostate cancer (34)(35)(36)(37)(38)(39)(40). This negative correlation between RBM3 expression and tumor progression does not seem to support its oncogenic function but is in agreement with the present results showing decreased RBM3 expression in metastatic prostate cancer compared with primary cancer and, more importantly, that overexpression of RBM3 in PC3 cells greatly attenuates the stem cell-like feature of this aggressive cell line.…”