Molecular stratification within triple-negative breast cancer subtypes.

Abstract

Triple-negative breast cancer (TNBC) has been subdivided into six distinct subgroups: basal-like 1 (BL1), basal-like 2 (BL2), mesenchymal (M), mesenchymal stem-like (MSL), immunomodulatory (IM), and luminal androgen receptor (LAR). We recently identified a subgroup of TNBC with loss of the tumor suppressor PTEN and five specific microRNAs that exhibits exceedingly poor clinical outcome and contains TP53 mutation, RB1 loss and high MYC and WNT signalling. Here, show that these PTEN-low/miRNA-low lesions cluster with BL1 TNBC. These tumors exhibited high RhoA signalling and were significantly stratified on the basis of PTEN-low/RhoA-signalling-high with hazard ratios (HRs) of 8.2 (P = 0.0009) and 4.87 (P = 0.033) in training and test cohorts, respectively. For BL2 TNBC, we identified AKT1 copy gain/high mRNA expression as surrogate for poor prognosis (HR = 3.9; P = 0.02 and HR = 6.1; P = 0.0032). In IM, programmed cell death 1 (PD1) was elevated and predictive of poor prognosis (HR = 5.3; P = 0.01 and HR = 3.5; P < 0.004). Additional alterations, albeit without prognostic power, characterized each subtype including high E2F2 and TGFβ signalling and CXCL8 expression in BL2, high IFNα and IFNγ signalling and CTLA4 expression in IM, and high EGFR signalling in MSL, and may be targeted for therapy. This study identified PTEN-low/RhoA-signalling-high, and high AKT1 and PD1 expression as potent prognostications for BL1, BL2 and IM subtypes with survival differences of over 14, 2.75 and 10.5 years, respectively. This intrinsic heterogeneity could be exploited to prioritize patients for precision medicine.

• Authors: Dong-Yu Wang, Zhe Jiang, Yaacov Ben-David, James R Woodgett, Eldad Zacksenhaus
• Journal: Scientific reports (Sci Rep) Vol. 9 Issue 1 Pg. 19107 (12 13 2019) ISSN: 2045-2322 [Electronic] England
• PMID: 31836816 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• AR protein, human
• MYC protein, human
• MicroRNAs
• Proto-Oncogene Proteins c-myc
• RB1 protein, human
• Receptors, Androgen
• Retinoblastoma Binding Proteins
• TP53 protein, human
• Tumor Suppressor Protein p53
• Wnt Proteins
• Ubiquitin-Protein Ligases
• PTEN Phosphohydrolase
• PTEN protein, human

Topics

• Cluster Analysis
• Computational Biology
• Databases, Factual
• Female
• Gene Dosage
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• MicroRNAs (metabolism)
• PTEN Phosphohydrolase (metabolism)
• Prognosis
• Proto-Oncogene Proteins c-myc (metabolism)
• Receptors, Androgen (metabolism)
• Retinoblastoma Binding Proteins (metabolism)
• Signal Transduction
• Treatment Outcome
• Triple Negative Breast Neoplasms (classification, diagnosis, genetics)
• Tumor Suppressor Protein p53 (metabolism)
• Ubiquitin-Protein Ligases (metabolism)
• Wnt Proteins (metabolism)