Abstract
With the exception of non-melanoma skin cancer, breast cancer is the most frequently diagnosed malignant disease among women, with the majority of mortality being attributable to metastatic disease. Thus, even with improved early screening and more targeted treatments which may enable better detection and control of early disease progression, metastatic disease remains a significant problem. While targeted therapies exist for breast cancer patients with particular subtypes of the disease (Her2+ and ER/PR+), even in these subtypes the therapies are often not efficacious once the patient's tumor metastasizes. Increases in stemness or epithelial-to-mesenchymal transition (EMT) in primary breast cancer cells lead to enhanced plasticity, enabling tumor progression, therapeutic resistance, and distant metastatic spread. Numerous signaling pathways, including MAPK, PI3K, STAT3, Wnt, Hedgehog, and Notch, amongst others, play a critical role in maintaining cell plasticity in breast cancer. Understanding the cellular and molecular mechanisms that regulate breast cancer cell plasticity is essential for understanding the biology of breast cancer progression and for developing novel and more effective therapeutic strategies for targeting metastatic disease. In this review we summarize relevant literature on mechanisms associated with breast cancer plasticity, tumor progression, and drug resistance.
Highlights
With the exception of non-melanoma skin cancer, breast cancer is the most frequently diagnosed malignant disease among women (Bray et al, 2018)
Nieto et al demonstrated that the homeobox transcription factor Prrx1, which induced epithelial-to-mesenchymal transition (EMT) and enabled invasiveness characteristics in a panel of human cancer cell lines, needed to be lost in order for breast cancer cells to metastasize in vivo
In line with this data, and importantly in the setting of the human disease, Maheswaran and colleagues found that mesenchymal cells expressing known EMT regulators, including TGF-β pathway components and the FOXC1 transcription factor, were highly enriched in circulating tumor cells (CTCs) and these mesenchymal CTCs were associated with disease progression (Yu et al, 2013)
Summary
Specialty section: This article was submitted to Molecular Diagnostics and Therapeutics, a section of the journal Frontiers in Molecular Biosciences. With the exception of non-melanoma skin cancer, breast cancer is the most frequently diagnosed malignant disease among women, with the majority of mortality being attributable to metastatic disease. While targeted therapies exist for breast cancer patients with particular subtypes of the disease (Her2+ and ER/PR+), even in these subtypes the therapies are often not efficacious once the patient’s tumor metastasizes. Increases in stemness or epithelial-to-mesenchymal transition (EMT) in primary breast cancer cells lead to enhanced plasticity, enabling tumor progression, therapeutic resistance, and distant metastatic spread. Understanding the cellular and molecular mechanisms that regulate breast cancer cell plasticity is essential for understanding the biology of breast cancer progression and for developing novel and more effective therapeutic strategies for targeting metastatic disease. In this review we summarize relevant literature on mechanisms associated with breast cancer plasticity, tumor progression, and drug resistance
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