Low-dose doxorubicin drives caveolin-1 depended re-epithelialization of breast cancer cells as a mechanism of cancer plasticity

Breast cancer cells undergo significant changes in their membrane organization, epithelial phenotype, and autophagy when exposed to low-dose doxorubicin chemotherapy over a prolonged period, according to a recent study. Researchers investigated the effects of sustained low-dose doxorubicin on mesenchymal-like MDA-MB-231 breast cancer cells.

The findings revealed that the low-dose doxorubicin treatment led to a notable increase in Caveolin-1 expression and an upsurge in E-cadherin protein levels. These changes were accompanied by a shift towards a more compact epithelial-like morphology, characterized by an increase in cell-cell contacts.

Live-cell imaging demonstrated that the membrane-to-cytoplasm fluorescence ratio of the lipid-anchored GFP-tH probe decreased significantly following treatment. This reduction indicated a redistribution of the lipid-anchored component from the plasma membrane to the cytoplasm. Moreover, analysis of autophagy-related proteins showed a decrease in LC3-I together with an increase in LC3-II, ATG5, and p62 expression. This pattern was consistent with the accumulation of autophagosomes and impaired autophagic flux.

The researchers concluded that low-dose doxorubicin promotes extensive remodeling of plasma membrane organization, epithelial plasticity, membrane-associated lipid-anchor localization, and autophagy in breast cancer cells. These findings unveil previously unrecognized links between membrane architecture, Ras membrane association, and autophagy during the phenotypic reprogramming of breast cancer cells.

The study provides valuable mechanistic insights into the cellular adaptations induced by sub-cytotoxic doxorubicin exposure.