The JAK2/STAT3 signaling pathway is required for growth of CD44+CD24– stem cell–like breast cancer cells in human tumors
Lauren L.C. Marotta, … , David A. Frank, Kornelia Polyak
Lauren L.C. Marotta, … , David A. Frank, Kornelia Polyak
Published June 1, 2011
Citation Information: J Clin Invest. 2011;121(7):2723-2735. https://doi.org/10.1172/JCI44745.
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Research Article

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

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.

Authors

Lauren L.C. Marotta, Vanessa Almendro, Andriy Marusyk, Michail Shipitsin, Janina Schemme, Sarah R. Walker, Noga Bloushtain-Qimron, Jessica J. Kim, Sibgat A. Choudhury, Reo Maruyama, Zhenhua Wu, Mithat Gönen, Laura A. Mulvey, Marina O. Bessarabova, Sung Jin Huh, Serena J. Silver, So Young Kim, So Yeon Park, Hee Eun Lee, Karen S. Anderson, Andrea L. Richardson, Tatiana Nikolskaya, Yuri Nikolsky, X. Shirley Liu, David E. Root, William C. Hahn, David A. Frank, Kornelia Polyak

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Figure 7

Specific activation of Stat3 in CD44+CD24– cells in primary human breast tumors.

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Specific activation of Stat3 in CD44+CD24– cells in primary human breast...
(A) Representative immunofluorescence staining patterns for CD44, CD24, and pStat3 in primary human breast tumor samples in each of the 4 indicated cell types. pStat3 is primarily in CD44+CD24– cells. Scale bars: 10 microns. (B) Frequency of pStat3 positivity in the indicated breast cancer cell types in 170 samples analyzed by triple immunofluorescence. (C) Box plots showing cells of 4 types positive for pStat3 based on triple immunofluorescence in 4 breast tumor subtypes. Triangles mark averages. *P < 0.001. (D) Model of Stat3 activation in breast cancer. CD44+CD24– stem cell–like cancer cells have constitutive pStat3 due to expression of genes such as IL6, PTGIS, and HAS1. Other cancer cells are sometimes pStat3+ due to uptake of IL-6 secreted by CD44+CD24– cancer cells, fibroblasts, and inflammatory cells.