Abstract
Breast cancer progression is highly dependent on the heterotypic interaction between tumor cells and stromal cells of the tumor microenvironment. Cancer-associated adipocytes (CAAs) are emerging as breast cancer cell partners favoring proliferation, invasion, and metastasis. This article discussed the intersection between extracellular signals and the transcriptional cascade that regulates adipocyte differentiation in order to appreciate the molecular pathways that have been described to drive adipocyte dedifferentiation. Moreover, recent studies on the mechanisms through which CAAs affect the progression of breast cancer were reviewed, including adipokine regulation, metabolic reprogramming, extracellular matrix remodeling, and immune cell modulation. An in-depth understanding of the complex vicious cycle between CAAs and breast cancer cells is crucial for designing novel strategies for new therapeutic interventions.
Highlights
Breast cancer (BC) is the most common cancer in women and the leading cause of mortality for women with cancers worldwide [1]
Insulin is a hormone involved in the differentiation of adipocytes other than their metabolic features through the activation of an intracellular signaling cascade involving the insulin receptor (IR), insulin receptor substrate (IRS) proteins, phosphoinositol 3-kinase (PI3K), and protein kinase B (AKT)
In addition to the adipokines mentioned above, there are multiple growth factors, cytokines, and chemokines produced by Cancer-associated adipocytes (CAAs) [110], which are implicated in a vicious cycle between adipocytes and BC cells in the tumor microenvironment (TME), inducing proliferation and metastasis, such as visfatin and resistin [111], CCL2 and CCL5, insulin-growth factor 1 (IGF-1) [112], hepatocyte growth factor (HGF), insulin-like growth factor binding protein 2 (IGFBP2) [113], TGFβ, vascular endothelial growth factor (VEGF), TNFα, as well as granulocyte colony-stimulating factor (G-CSF) [114]
Summary
Breast cancer (BC) is the most common cancer in women and the leading cause of mortality for women with cancers worldwide [1]. Adipocytes are the main stromal cells in the breast, and research in recent decades has provided evidence that they are not just terminally differentiated cells impassive to the external environment Besides differentiation, they can undergo dedifferentiation and trans-differentiation in many physiological processes, as well as in pathological conditions [4]. The intimate crosstalk between cancer cells and adipocytes induces their dedifferentiation in terms of a reduction of terminal differentiation with a reduction and increase in the expression of differentiation markers and several pro-tumoral molecules, respectively. Due to their contribution to tumor cell aggressiveness, tumor-modified adipocytes have been named cancer-associated adipocytes (CAAs) [10]. The role of tumor-secreted molecules in this interaction will be discussed with a focus on pathways already described to be relevant in the adipogenesis process
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