Abstract
Secreted microRNAs (miRNAs) reside in a complex regulatory network with extracellular matrix (ECM) macromolecules, which affect cell-cell communication, therefore miRNA expression highlights its significance in several aspects of human diseases, including cancer. miRNA-mediated regulation of breast cancer has received considerable attention due to evidence that shows miRNAs to mediate estrogen receptor (ER) status, metastasis, chemoresistance and epithelial-to-mesenchymal transition (EMT). miR-200b is a pluripotent miRNA, which is inversely regulated by ERα and ERβ in mammary cancer. It has been identified as tumor suppressor and EMT inhibitor serving as a critical biomarker, as its expression in breast tumor determines the disease-free survival, thus highlighting its roles in breast cancer invasion and metastasis. The main goal of this study was to investigate the role of miR-200b in modulating the behavior of breast cancer cells with different ER status. We demonstrate that estrogen signaling through ERs reduces miR-200b expression levels in ERα-positive breast cancer cells. Moreover, miR-200b upregulation reduces the aggressive phenotype of ERβ-positive breast cancer cells by inhibiting cell invasiveness and motility, followed by ECM reorganization as well as cytoskeletal and morphological changes concluded from deep inspection of cell topography. Future investigation towards the mechanistic perspective of miR-200b effects in the behavior of aggressive mammary cancer cells appears rewarding in order to expand our understanding of miR-200b as a novel mediator beyond breast cancer diagnosis and pharmaceutical targeting.
Highlights
With approximately 1,676,600 new cases per year worldwide, breast cancer is the most frequent malignancy in women [1]
Among the deregulated miRNAs, miR-200 family has been studied in several cancer types including breast cancer [31]. miR-200b serves as a pluripotent miRNA with important roles in regulating breast cancer aggressiveness, highlighting its prominent diagnostic and therapeutic potential in breast cancer
Our study extends these findings to the subgroup of ERpositive systemically treated breast cancer patients, where a high expression of miR-200b was associated with a better survival. miR-200b has been linked to the mesenchymal characteristics of mammary carcinoma cells acting as a negative regulator of tumor invasion and metastasis [28]
Summary
With approximately 1,676,600 new cases per year worldwide, breast cancer is the most frequent malignancy in women [1]. Breast cancer mortality is closely linked to the process of metastasis to vital organs [5]. Metastasis is promoted both by tumor cell-autonomous changes in cell motility and by close interactions of cancer cells with their extracellular and cellular microenvironment, which drive metastatic behavior [4,5,6,7]. Constitutive signaling mutations and upregulation of chemokine, angiogenesis and growth factor receptors and their ligands, as well as remodeling processes that affect ECM stiffness, promote breast cancer cell motility, chemotaxis to distant sites and angiogenesis as a prerequisite for dissemination of tumor cells via blood circulation [9,10]. The ECM plays an important role in EMT, as proteoglycans (PGs) modulate important EMT-promoting signaling pathways [13,14], such as the transforming growth factor beta (TGFβ) and interleukin-6 (IL-6) pathways [15,16], affect the expression of the anti-invasive, epithelial homotypic cell-adhesion molecule, E-cadherin [15,17] and mediate ECM remodeling and fibrillar alignment of the ECM in the peritumoral stroma [7,11]
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