WNT signaling pathway regulator-FRAT2 affects oncogenesis and prognosis of basal-like breast cancer

Abstract

Background: Breast cancer is the most common malignant cancer in women worldwide and is one of the leading causes of cancer death. Basal-like breast cancer (BLBC) is an aggressive subtype of breast cancer for which targeted therapy has poor efficacy. Therefore, research into the molecular pathogenesis of BLBC is urgent for developing effective targeted therapeutic treatments. Methods: We collected relevant data from the Cancer Genome Atlas (TCGA), including transcriptome, copy number variation, and survival data. We also gathered 30 pairs clinical samples of cancer tissues and non-cancerous tissues to perform Western Blotting (WB) to reveal the encoded protein expression levels.Besides, we knocked down frequently rearranged in advanced T-cell lymphomas 2 (FRAT2) expression in two representative cell lines (T47D and MDA-MB-231 cells). The cell cycle progression was analyzed, while the apoptosis experiments were also conducted to explore the molecular pathogenesis of FRAT2 in BLBC. Results: The aberrant activation of the WNT pathway and highly expressed FRAT2 were specifically identified across the BLBC genome comparing to other types of tumor. In addition, FRAT2 expression was found to be positively associated with its copy number variations (P=9.126×10 −23). For further investigation,we found the expression level of FRAT2 was related to the poor overall survival of BLBC patients (P=0.049).The results of WB revealed that FRTA2-encoded protein was overexpressed in BLBC tissues. Based on results in T47D and MDA-MB-231 cells in vitro, we found that knocking down FRAT2 can inhibit the proliferation of these two cell lines. In cell cycle progression experiments, cell cycle arrested in the G2/M phase. Meanwhile, increased apoptosis was also found in the shFRAT2 cell group in vitro.Conclusions: In BLBC basal-like breast cancer, we can assume that FRAT2 is a potential treatment target.

The miR-3648/FRAT1-FRAT2/c-Myc negative feedback loop modulates the metastasis and invasion of gastric cancer cells

“…The FRAT1 and FRAT2 genes are clustered in the human chromosome locus 10q24.1, and both genes have been previously identified as proto-oncogenes in a variety of tumours [ 11 , 30 , 36 ], including basal-like breast cancer [ 49 ], ovarian cancer [ 37 ], and GC [ 30 ]. However, whether miR-3648 participates in the regulation of FRAT1 or FRAT2 expression in GC remains unknown.…”

Leveraging Deep Learning Techniques and Integrated Omics Data for Tailored Treatment of Breast Cancer

“…Additionally, BLBC patients have poor survival because their tumours often have an incomplete pathological response to treatment. Studies have also shown that the EGFR gene is highly expressed in up to 78% of BLBC cases [ 37 ], but clinical trials have not shown great improvement using EGFR targeted therapy [ 36 ], mainly because EGFR downstream signalling pathways were still activated in most patients after EGFR-targeted treatment. This fact implies that there might be other pathways involved in bypass activation.…”

“…The BLBC subtype has abnormal expression of MYC, PIK3CA, CDK6, AKT2, KRAS, FGFR1, IGF1R, CCNE1, CDKN2A/B, BRCA2, BRAF, PTEN, MDM2, RB1, TP53, EGFR, MET, NGF and HDAC1. Possible drugs for this subtype include growth factor inhibitors, DNA synthetic inhibitors, PARP inhibitors, genotoxic agents, mTOR inhibitors, histone deacetylase inhibitors, CDK inhibitors and other inhibitors depending on the target, as summarized in Table 4 [ 36 , 37 , 38 ]. The targeted drug selection delivery strategies require more clinical trial results to validate studies.…”

“…The class of drugs identified for BLBC includes CDK inhibitors, histone deacetylase inhibitors, receptor tyrosine kinase inhibitors, BRAF inhibitors, mitosis inhibitors, DNA synthetic inhibitors, PARP inhibitors, growth factor inhibitors, mTOR inhibitors, etc. Recent investigations have also suggested the aforementioned inhibitors [ 37 , 42 ]. Whether a response to therapy is beneficial to the patient’s ultimate treatment routine is still a matter of debate.…”

Prognostic signature of ovarian cancer based on 14 tumor microenvironment-related genes

“…[ 39 ] Increased expression of FRAT2 is observed in multiple cancers, such as the gastric cancer and lung cancer, which is probably associated with the regulation of WNT signaling pathway. [ 40 , 41 ] WDR45 encodes the beta-propeller protein, and its mutation occurs in cancers including endometrial carcinoma and clear cell renal carcinoma. [ 42 , 43 ] ADSL plays a key role in the de novo purine synthesis pathway, and is an oncogenic driver in several cancers, thus being considered as an essential therapeutic target in cancer.…”