The JAK2/STAT3 signaling pathway is required for growth of CD44+CD24– stem cell–like breast cancer cells in human tumors

TLDR

Intratumor heterogeneity causes variable therapeutic sensitivity and distinct roles in progression, and two breast tumor subpopulations—CD44+CD24− stem‑like cells and CD44−CD24+ differentiated cells—have been characterized. A loss‑of‑function screen identified 15 genes essential for CD44+CD24− breast cancer cell growth, and knockdown of IL‑6, PTGIS, HAS1, CXCL3, or PFKFB3 lowered Stat3 activation. The IL‑6/JAK2/Stat3 pathway is preferentially active in CD44+CD24− cells, and JAK2 inhibition reduces their numbers and blocks xenograft growth, underscoring JAK2 and Stat3 as promising therapeutic targets.

Abstract

Intratumor heterogeneity is a major clinical problem because tumor cell subtypes display variable sensitivity to therapeutics and may play different roles in progression. We previously characterized 2 cell populations in human breast tumors with distinct properties: CD44+CD24- cells that have stem cell-like characteristics, and CD44-CD24+ cells that resemble more differentiated breast cancer cells. Here we identified 15 genes required for cell growth or proliferation in CD44+CD24- human breast cancer cells in a large-scale loss-of-function screen and found that inhibition of several of these (IL6, PTGIS, HAS1, CXCL3, and PFKFB3) reduced Stat3 activation. We found that the IL-6/JAK2/Stat3 pathway was preferentially active in CD44+CD24- breast cancer cells compared with other tumor cell types, and inhibition of JAK2 decreased their number and blocked growth of xenografts. Our results highlight the differences between distinct breast cancer cell types and identify targets such as JAK2 and Stat3 that may lead to more specific and effective breast cancer therapies.