Molecular markers associated with the outcome of tamoxifen treatment in estrogen receptor-positive breast cancer patients: scoping review and in silico analysis

Abstract

Tamoxifen (TMX) is used as adjuvant therapy for estrogen receptor-positive (ER+) breast cancer cases due to its affinity and inhibitory effects. However, about 30% of cases show drug resistance, resulting in recurrence and metastasis, the leading causes of death. A literature review can help to elucidate the main cellular processes involved in TMX resistance. A scoping review was performed to find clinical studies investigating the association of expression of molecular markers profiles with long-term outcomes in ER+ patients treated with TMX. In silico analysis was performed to assess the interrelationship among the selected markers, evaluating the joint involvement with the biological processes. Forty-five studies were selected according to the inclusion and exclusion criteria. After clustering and gene ontology analysis, 23 molecular markers were significantly associated, forming three clusters of strong correlation with cell cycle regulation, signal transduction of proliferative stimuli, and hormone response involved in morphogenesis and differentiation of mammary gland. Also, it was found that overexpression of markers in selected clusters is a significant indicator of poor overall survival. The proposed review offered a better understanding of independent data from the literature, revealing an integrative network of markers involved in cellular processes that could modulate the response of TMX. Analysis of these mechanisms and their molecular components could improve the effectiveness of TMX.

Keywords: Biological processes; Breast cancer; HR positive; Molecular targets; Recurrence; Tamoxifen.

Fig. 1

PRISMA diagram of selection of studies and in silico analysis. The upper section corresponds to the step-by-step manuscript selection process according to the established inclusion and exclusion criteria. The Lower section includes the sequence of in silico analysis performed with all selected biomarkers to search a better and integrated understanding of the influence of each protein in TMX resistance

Fig. 2

In silico analysis. A 3 clusters were formed with strongly linked molecular markers, cluster 1(red), cluster 2 (green), and cluster 3 (blue). The markers in gray were not included in the clusters, remaining just interconnected proteins among clusters inside the network. B unconnected markers. A and B still reveal the functional status of each molecular marker. 12 markers (dashed borderline in the molecular markers) decrease in functional activity associated to poor outcomes in BC patients, the other 33 markers presented an elevated functional activity associated to worst outcomes (full borderline in the molecular markers), accordingly information of their original manuscripts. C Gene ontology analysis for biological processes: CLUSTER 1 presented significant involvement with molecular events related to cell proliferation, CLUSTER 2 with the modulation of proliferative mechanisms, and CLUSTER 3 with the mammary gland development and its hormone stimulation. D Genetic ontology analysis of clusters 2 and 3, taking into account not only its constituent markers but with its direct neighbors

Fig. 3

Predictive analysis of overall survival for each set of markers in BC patients using the Kaplan–Meier plotter tool. A Analysis of all 45 selected markers. B Only the networked markers (23 markers). C Unconnected markers (22 markers). D Analysis of clusters 1, 2, and 3. E Cluster 2 and 3 with their direct neighbors. Significant p-values (< 0.05) are highlighted in bold