Regulation of cellular heterogeneity and symmetric/asymmetric divisions in triple-negative breast cancer

Differentiation events contribute to cellular heterogeneity within tumors and influence disease progression and response to therapy. Here we dissect mechanisms controlling intratumoral heterogeneity within triple-negative basal-like breast cancers. Tumor cells expressing the cytokeratin K14 possess a differentiation state that is associated with that of normal luminal progenitors, while K14-negative cells are in a state closer to that of mature luminal cells. We show that cells can transition between these states through asymmetric divisions, which produce one K14 + and one K14 – daughter cell, and that these asymmetric divisions contribute to the generation of cellular heterogeneity. We identified several regulators that control the proportion of K14 + cells in the population. EZH2 and Notch increase the numbers of K14 + cells and their rates of symmetric divisions, while FOXA1 has an opposing effect. Our findings demonstrate a role for asymmetric divisions as a mechanism for differentiation transitions, and identifypathways that control breast cancer cellular composition. The data shows WGS of HCC70 cells sorted into K14-positive and K14-Negative populations.