Cellular Plasticity in Breast Cancer Progression and Therapy

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.

EpCAM-Mediated Cellular Plasticity Promotes Radiation Resistance and Metastasis in Breast Cancer

“…Further, the dynamic nature of heterogeneity due to cellular plasticity at different stages of resistance development complicates the matter. The numbers of CSCs within a cell population also varies and part of this dynamicity is known to be contributed by various extrinsic and intrinsic factors ( Kong et al, 2020 ). Here, by isolating CSC subpopulations by cell sorting, we found that they are less susceptible to the radiation (extrinsic factor) induced DNA damage and survive better.…”

“…Thus, the wheel tilts more toward a dynamic cellular adaptive response like radiation induced metastasis of BC cells or selection of a highly metastatic clones, as plausible reasons behind increased cases of metastasis. In this regard, the cellular plasticity concept has evolved against various therapeutic assaults ( Elshamy and Duhe, 2013 ; Arnold et al, 2020 ; Kong et al, 2020 ). We have been investigating on aspects of BC radioresistance with an aim to resolve the dichotomy between the purpose and outcome of RT protocol ( Desai et al, 2018 ).…”

Hemoglobin overexpression and splice signature as new features of inflammatory breast cancer?

“…Several recent studies suggest that breast cancer stem cells (BCSCs) can be derived from differentiated mammary cells due to gene mutations, a damaging physical stimulus, or the tissue microenvironment and not necessary from mammary stem cells or progenitor cells. The enhanced tumor plasticity through this gain in stem cells clearly favours progression and metastasis [35] . Targeting plasticity may represent a promising approach to repress metastasis and treat IBC.…”

Regulating Methylation at H3K27: A Trick or Treat for Cancer Cell Plasticity

“…Indeed, in vivo administration of a dual KDM6- and LSD1-targeted inhibitor, MC3324, suppresses growth of ER-dependent breast cancers [ 343 ]. Conversely, KDM6 activity can also be associated with loss of proliferation as entrance of glioblastoma stem cells into a reversible, drug-tolerant, slow-cycling state is dependent on up-regulation and activity of KDM6A and KDM6, which can be prevented by GSK-J4, an inhibitor of both enzymes [ 344 , 345 ].…”