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, 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
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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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 2

Identification and validation of genes required in basal-like breast cancer cells.

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Identification and validation of genes required in basal-like breast can...
(A) Robust z test scores ([average viability – plate median average viability]/[plate median absolute deviation of average viability]) from shRNA screen, phase 1, for shRNAs with infection efficiencies greater than 0.25 and robust z test score SD below the 99th percentile for both basal-like and luminal cell lines with and without puromycin (puro). Data representing basal-like and luminal hits, selected based on their 4 basal-like or luminal robust z test scores as described in the text, are red and blue, respectively. (B) Scoring of shRNAs with infection efficiencies greater than 0.25 for all cell lines and classification of hits in shRNA screen, phase 2. Shading indicates shRNAs scored based on percentage of control values ([100 × average viability]/[median average viability of plate controls]). Genes corresponding to hits are listed. (C) Box plots showing viability of breast cell lines treated with siRNAs in triplicate for 3 days. Triangles mark averages. Circles mark outliers (which were included in P value calculations). *P < 0.05, t test; **P < 0.01, t test. (D) GI50 values for inhibitors in breast cell lines. The maximum percentage of growth inhibition observed is shown when cells were not affected enough for GI50 calculation. Error bars show SD of triplicates. All percentage growth inhibition data used to prepare these graphs are depicted in Supplemental Figure 2C.