Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features

TLDR

Breast cancers contain a small CD44⁺/CD24⁻/low subpopulation with high tumor‑initiating potential, and mammosphere cultures are similarly enriched for self‑renewing cells. The authors sought to determine whether residual tumor cells after standard therapy are enriched for a CD44⁺/CD24⁻/low‑mesenchymal signature and to propose that targeting EMT proteins could eradicate these cells to prevent recurrence. Residual breast tumors after endocrine or chemotherapy were enriched for a CD44⁺/CD24⁻/low‑mesenchymal signature, especially in claudin‑low tumors, with heightened expression of mesenchymal markers such as vimentin and MMP2, indicating that surviving cells possess both tumor‑initiating and mesenchymal traits.

Abstract

Some breast cancers have been shown to contain a small fraction of cells characterized by CD44(+)/CD24(-/low) cell-surface antigen profile that have high tumor-initiating potential. In addition, breast cancer cells propagated in vitro as mammospheres (MSs) have also been shown to be enriched for cells capable of self-renewal. In this study, we have defined a gene expression signature common to both CD44(+)/CD24(-/low) and MS-forming cells. To examine its clinical significance, we determined whether tumor cells surviving after conventional treatments were enriched for cells bearing this CD44(+)/CD24(-/low)-MS signature. The CD44(+)/CD24(-/low)-MS signature was found mainly in human breast tumors of the recently identified "claudin-low" molecular subtype, which is characterized by expression of many epithelial-mesenchymal-transition (EMT)-associated genes. Both CD44(+)/CD24(-/low)-MS and claudin-low signatures were more pronounced in tumor tissue remaining after either endocrine therapy (letrozole) or chemotherapy (docetaxel), consistent with the selective survival of tumor-initiating cells posttreatment. We confirmed an increased expression of mesenchymal markers, including vimentin (VIM) in cytokeratin-positive epithelial cells metalloproteinase 2 (MMP2), in two separate sets of postletrozole vs. pretreatment specimens. Taken together, these data provide supporting evidence that the residual breast tumor cell populations surviving after conventional treatment may be enriched for subpopulations of cells with both tumor-initiating and mesenchymal features. Targeting proteins involved in EMT may provide a therapeutic strategy for eliminating surviving cells to prevent recurrence and improve long-term survival in breast cancer patients.