Regulators of cellular heterogeneity in basal-like breast cancer influence symmetric versus asymmetric division rates (shRNA targeting)

Differentiation events contribute to cellular heterogeneity within tumors and influence disease progression and response to therapy. Here we dissect the mechanisms controlling intratumoral heterogeneity within basal-like breast cancers. We show that cancer cells can transition between a differentiation state related to that of normal luminal progenitors and a state closer to that of mature luminal cells, and that this occurs through asymmetric cell divisions. The Polycomb factor EZH2 and the Notch pathway act to increase the rates of symmetric divisions that produce progenitor-like cells, while the FOXA1 transcription factor promotes asymmetric divisions that reduce the numbers of such cells. Through functional screening, we identified a group of regulators that control cancer cell differentiation state and the relative proportions of tumor cell subpopulations. Our findings highlight the regulation of asymmetric cell divisions as a mechanism controlling intratumoral heterogeneity, and identify molecular pathways that control breast cancer cellular composition. Overall design: Expression profiles of HCC70 cells expressing shRNAs targeting regulatory factors that influence basal-like cancer cell population composition

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Granit RZ, Masury H, Condiotti R, Fixler Y, Gabai Y, Glikman T, Dalin S, Winter E, Nevo Y, Carmon E, Sella T, Sonnenblick A, Peretz T, Lehmann U, Paz K, Piccioni F, Regev A, Root DE, Ben-Porath I