Bioinformatic Study of Involved Mechanisms in Relapse and Drug Resistance of Tamoxifen-Treated Breast Cancer

Background: Breast cancer is currently among the most common cause of mortality in women. Estrogen and its subsequent signaling pathways play an important role in the occurrence of breast cancer relapse. Tamoxifen is the most common breast cancer treatment option in ER+ patients, which acts as an adjuvant endocrinotherapy with X-ray and surgery. This approach is recommended as the first line treatment and has increased the survival rate of breast cancer patients and reduced the relapse cases. However, we can observe resistance to tamoxifen and relapse cases in one-third of patients treated with this drug, which has become a major concern. Objective: The precise mechanisms of relapse and resistance to tamoxifen have not yet been identified and were explored in this study. Methods: Microarray profiles of relapse and relapse-free patients were investigated to explain the processes leading to relapse and possibly to tamoxifen resistance. Results: According to the preliminary analysis, 1460 genes showed increased expression and 1132 genes showed decreased expression. According to our default for inclusion (-2LogFC≥ + 2), 36 genes had increased expression (upregulated) and 33 genes had decreased expression (down-regulated). Conclusion: It seems that the mechanisms of resistance and relapse are multifactorial, and tumor cells induce relapse and resistance to tamoxifen through mechanisms of cell proliferation, survival, invasion, angiogenesis, extracellular matrix secretion, pump and membrane changes and immune evasion.

TCF7L2 plays a complex role in human adipose progenitor biology which may contribute to genetic susceptibility to type 2 diabetes

ABSTRACTNon-coding genetic variation at TCF7L2 is the strongest genetic determinant of type 2 diabetes (T2D) risk in humans. TCF7L2 encodes a transcription factor mediating the nuclear effects of WNT signalling in adipose tissue (AT). Here we mapped the expression of TCF7L2 in human AT and investigated its role in adipose progenitor (AP) biology. APs exhibited the highest TCF7L2 mRNA abundance compared to mature adipocytes and adipose-derived endothelial cells. Obesity was associated with reduced TCF7L2 transcript levels in subcutaneous abdominal AT but increased expression in APs. In functional studies, TCF7L2 knockdown (KD) in APs led to dose-dependent activation of WNT/β-catenin signaling, impaired proliferation and dose-dependent effects on adipogenesis. Whilst partial KD enhanced adipocyte differentiation, complete KD impaired lipid accumulation and adipogenic gene expression. Overexpression of TCF7L2 accelerated adipogenesis. Transcriptome-wide profiling revealed that TCF7L2 can modulate multiple aspects of AP biology including extracellular matrix secretion, immune signalling and apoptosis. The T2D-risk allele at rs7903146 was associated with reduced AP TCF7L2 expression and enhanced AT insulin sensitivity. Our study highlights a complex role for TCF7L2 in AP biology and suggests that in addition to regulating pancreatic insulin secretion, genetic variation at TCF7L2 may also influence T2D risk by modulating AP function.