Pathway-Centric Integrative Analysis Identifies RRM2 as a Prognostic Marker in Breast Cancer Associated with Poor Survival and Tamoxifen Resistance

Abstract

Breast cancer (BCa) molecular subtypes include luminal A, luminal B, normal-like, HER-2–enriched, and basal-like tumors, among which luminal B and basal-like cancers are highly aggressive. Biochemical pathways associated with patient survival or treatment response in these more aggressive subtypes are not well understood. With the limited availability of pathologically verified clinical specimens, cell line models are routinely used for pathway-centric studies. We measured the metabolome of luminal and basal-like BCa cell lines using mass spectrometry, linked metabolites to biochemical pathways using Gene Set Analysis, and developed a novel rank-based method to select pathways on the basis of their enrichment in patient-derived omics data sets and prognostic relevance. Key mediators of the pathway were then characterized for their role in disease progression. Pyrimidine metabolism was altered in luminal versus basal BCa, whereas the combined expression of its associated genes or expression of one key gene, ribonucleotide reductase subunit M2 (RRM2) alone, associated significantly with decreased survival across all BCa subtypes, as well as in luminal patients resistant to tamoxifen. Increased RRM2 expression in tamoxifen-resistant patients was verified using tissue microarrays, whereas the metabolic products of RRM2 were higher in tamoxifen-resistant cells and in xenograft tumors. Both genetic and pharmacological inhibition of this key enzyme in tamoxifen-resistant cells significantly decreased proliferation, reduced expression of cell cycle genes, and sensitized the cells to tamoxifen treatment. Our study suggests for evaluating RRM2-associated metabolites as noninvasive markers for tamoxifen resistance and its pharmacological inhibition as a novel approach to overcome tamoxifen resistance in BCa.

Targeting Ribonucleotide Reductase M2 and NF-κB Activation with Didox to Circumvent Tamoxifen Resistance in Breast Cancer

“…Our data suggest that combining didox with tamoxifen may offer significant benefits to patients with ER-positive breast cancer with high RRM2 expression or patients who have relapsed after long-term tamoxifen treatment. Similarly, RRM2 was recently suggested as a prognostic marker associated with poor survival and tamoxifen resistance, which supports our findings that RRM2 is an important contributor on the pathway to tamoxifen resistance (48).…”

Metabolomics Analysis of Hormone-Responsive and Triple-Negative Breast Cancer Cell Responses to Paclitaxel Identify Key Metabolic Differences

“…Also, CA-derived TNBC cells (MDA-MB-231) are metabolically different from AA-derived TNBC cells (MDA-MB-468). As demonstrated previously in both cell-based 42, 94 or xenograft 95 models and in human subjects samples, 40–41 our data continue to confirm metabolomic profiling as a suitable technology to distinguish the clinical subtypes of BCa under non-treated conditions or following treatment. Biochemical pathway enrichment analyses revealed novel and potentially relevant pathways contributing to the biology that distinguishes the cell lines or that were perturbed in response to drug treatment depending on the cell line and type.…”

Network-based approach to identify prognostic biomarkers for estrogen receptor–positive breast cancer treatment with tamoxifen

“…36 Although considerable information on ER and breast cancer has been provided since the availability of tamoxifen in clinical Recurrence free survival (RFS), Distant metastasis free survival (DMFS). Hazard ratios (HRs), 95% confidence intervals (CI), and p-values were calculated using Cox proportional hazards regression analysis after grouped the breast cancer patients by the median of gene level.…”