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 1

Characteristics of genes and cell lines chosen for shRNA screen.

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Characteristics of genes and cell lines chosen for shRNA screen. (A) Clu...
(A) Clustering of SAGE data for the genes in the screen. Genes were selected based on their differential expression between the groups of samples of CD44+CD24– and CD44–CD24+ (primary tumor) cells shown. Red and green (in A and B) indicate high and low gene expression, respectively. PE, pleural effusion; ASC, ascites; IDC, invasive ductal carcinoma. (B) Clustering of previously published microarray data (63) for 54 breast cell lines using the genes in the screen. Clusters of basal-like and luminal cell lines were formed. The 14 cell lines highlighted in bold were chosen for the screen. (C) Expression of CD44 and CD24 in the cell lines used in the screen. Results of flow cytometry analysis of CD44 and CD24 levels are shown. Flow cytometry profiles and gating are shown in Supplemental Figure 1. (D) qMSP data for the cell lines included in the screen for genes differentially methylated between CD44+CD24– and CD44–CD24+ breast cancer cells (as shown at right). Each bar represents the natural log of the ratio of the qMSP reading of either FOXC1, HOXA10, or PACAP (official gene symbol, MGC29506) to the qMSP reading of SLC9A3R1. Error bars show SD of triplicates (for cell lines) or 3 ER+PR+HER2– tumor samples (for primary tumor cells). Asterisks indicate the cell lines that were chosen for phase 1 of the screen based on these results and the ease of their growing in culture.