Upregulation of lipid metabolism genes in the breast prior to cancer diagnosis

Abstract

Histologically normal tissue adjacent to the tumor can provide insight of the microenvironmental alterations surrounding the cancerous lesion and affecting the progression of the disease. However, little is known about the molecular changes governing cancer initiation in cancer-free breast tissue. Here, we employed laser microdissection and whole-transcriptome profiling of the breast epithelium prior to and post tumor diagnosis to identify the earliest alterations in breast carcinogenesis. Furthermore, a comprehensive analysis of the three tissue compartments (microdissected epithelium, stroma, and adipose tissue) was performed on the breast donated by either healthy subjects or women prior to the clinical manifestation of cancer (labeled “susceptible normal tissue”). Although both susceptible and healthy breast tissues appeared histologically normal, the susceptible breast epithelium displayed a significant upregulation of genes involved in fatty acid uptake/transport (CD36 and AQP7), lipolysis (LIPE), and lipid peroxidation (AKR1C1). Upregulation of lipid metabolism- and fatty acid transport-related genes was observed also in the microdissected susceptible stromal and adipose tissue compartments, respectively, when compared with the matched healthy controls. Moreover, inter-compartmental co-expression analysis showed increased epithelium-adipose tissue crosstalk in the susceptible breasts as compared with healthy controls. Interestingly, reductions in natural killer (NK)-related gene signature and CD45+/CD20+ cell staining were also observed in the stromal compartment of susceptible breasts. Our study yields new insights into the cancer initiation process in the breast. The data suggest that in the early phase of cancer development, metabolic activation of the breast, together with increased epithelium-adipose tissue crosstalk may create a favorable environment for final cell transformation, proliferation, and survival.

Obese Adipose Tissue as a Driver of Breast Cancer Growth and Development: Update and Emerging Evidence

“…In a recent study, microdissection was performed on epithelium, adipose tissue, and stroma in breast sections from women before and after breast cancer diagnosis. Co-expression network analyses comparing tissue associations between compartments showed increased interaction between the epithelial compartment and surrounding adipose tissue prior to breast cancer development, confirming the existence of a crosstalk between breast epithelial cells and adjacent adipose tissue (19). This is a significant finding since in the setting of obesity, breast adipose tissue undergoes considerable dysregulation in the production of estrogens, adipokines, inflammatory mediators, and reactive oxygen species (ROS), creating a microenvironment primed for initiating breast cancer development and promoting progression (Figure 1).…”

“…Another study also implicated leptin in the early stages of breast cancer, showing that leptin treatment promotes epithelial-mesenchymal transition through activation of the kinases Src and FAK in MCF10A cells, a non-cancerous mammary epithelial cell line, which led to enhanced invasion through Matrigel ( 80 ). In a study of normal breast epithelium from women before and after breast cancer diagnosis compared with women who never developed breast cancer, leptin was upregulated 3.8 fold in the breast epithelium before cancer diagnosis, suggesting that increased leptin may be an early event associated with epithelial cell transformation ( 19 ).…”

Metabolic Reprogramming: A Friend or Foe to Cancer Therapy?

“…The complexities of p53 regulating metabolic reprogramming are further compounded by tissue-specific differences in metabolic programmes [48]. Breast and lung cancer are both considered to be somewhat p53 driven [49] but show vastly different dependencies on lipid metabolism for tumour growth [50][51][52]. Hence p53 status should not be considered in isolation but must be examined in the wider context alongside other driver mutations and tissue metabolic demands.…”

Towards More Predictive, Physiological and Animal-free In Vitro Models: Advances in Cell and Tissue Culture 2020 Conference Proceedings

“…Furthermore, adipose tissue was identified as potentially having a more prominent role in breast cancer development and progression; a view that is also being increasingly shared by others. 51,52 Raising an aptamer against the peptide hormone, kisspeptin, for potential diagnostic use in Alzheimer's disease and ovarian cancer Ms Sheree Smith (Leeds Beckett University, UK) described the synthesis of a non-animalderived affinity reagent (ssDNA aptamer) against the peptide hormone, kisspeptin. This aptamer could be used for research and diagnostic purposes in Alzheimer's disease and ovarian cancer.…”