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

Maiquidieli Dal Berto,Ivana Beatrice Mânica da Cruz,José Eduardo Vargas,Fernanda Barbisan,Giovana Tavares dos Santos,Andrew Oliveira Silva,Claudia Giuliano Bica,Rafael José Vargas Alves,Aniúsca Vieira dos Santos

doi:10.1007/s12672-021-00432-7

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.

Highlights

Breast cancer (BC) is the most prevalent cancer among women in developed and developing countries [1]
About 60 to 70% of all diagnosed BC are positive for hormone receptor expression (HR+), estrogen receptor (ER+) and/ or progesterone receptor (PR+)
The main excluding factors were: (1) in vitro experimentation; (2) in vivo assays; (3) clinical studies assessing less than 35 patients (4) the absence of prognostic factor assessing in clinical studies; (5) the absence of hormone therapy with TMX; (6) manuscripts using of transcription or genomic sequencing data deposited in public databases; (7) works testing other types of hormone therapy, differently of TMX; (8) and review manuscripts

Summary

Introduction

Breast cancer (BC) is the most prevalent cancer among women in developed and developing countries [1]. Due to its incidence and mortality, it is considered a serious public health problem worldwide [2, 3]. This type of cancer is a complex and heterogeneous disease with several distinct histopathological and molecular subtypes. About 60 to 70% of all diagnosed BC are positive for hormone receptor expression (HR+), estrogen receptor (ER+) and/ or progesterone receptor (PR+). The stimulation of both receptors by its ligand molecules—estrogen and progesterone—induces mainly transcriptional changes, which trigger biological processes such as cell survival, proliferation, and differentiation. In breast cancer, its constant stimulation by sexual hormones could contribute to tumor increasing and disease progression [4, 5], justifying anti-estrogen therapies as an adjuvant treatment for this type of neoplasia [6]

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Conclusion