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

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

doi:10.1172/jci44745

Cited by 780 publications

(746 citation statements)

References 63 publications

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“…It is also noteworthy that STAT3 activation is observed in stem cell-like cancer cells from different molecular subtypes of breast cancer and targeting JAK2 is effective to treat the triple-negative subtype in preclinical models. [48][49][50] Together, these results suggest a pivotal role for JAK2 irrespective of the receptors mediating activation and thus underscore a generalizable potential for JAK2-targeted therapy to treat multiple forms of this disease.…”

Section: Discussionmentioning

confidence: 76%

Dysregulated STAT1-SOCS1 control of JAK2 promotes mammary luminal progenitor cell survival and drives ERα+ tumorigenesis

et al. 2013

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We previously reported that STAT1 expression is frequently abrogated in human estrogen receptor-a-positive (ERa þ ) breast cancers and mice lacking STAT1 spontaneously develop ERa þ mammary tumors. However, the precise mechanism by which STAT1 suppresses mammary gland tumorigenesis has not been fully elucidated. Here we show that STAT1-deficient mammary epithelial cells (MECs) display persistent prolactin receptor (PrlR) signaling, resulting in activation of JAK2, STAT3 and STAT5A/ 5B, expansion of CD61 þ luminal progenitor cells and development of ERa þ mammary tumors. A failure to upregulate SOCS1, a STAT1-induced inhibitor of JAK2, leads to unopposed oncogenic PrlR signaling in STAT1 À / À MECs. Prophylactic use of a pharmacological JAK2 inhibitor restrains the proportion of luminal progenitors and prevents disease induction. Systemic inhibition of activated JAK2 induces tumor cell death and produces therapeutic regression of pre-existing endocrine-sensitive and refractory mammary tumors. Thus, STAT1 suppresses tumor formation in mammary glands by preventing the natural developmental function of a growth factor signaling pathway from becoming pro-oncogenic. In addition, targeted inhibition of JAK2 may have significant therapeutic potential in controlling ERa þ breast cancer in humans. Cell Death and Differentiation (2014) 21, 234-246; doi:10.1038/cdd.2013.116; published online 13 September 2013Estrogen receptor-a-positive (ERa þ ) breast cancer, the most commonly diagnosed subtype of breast malignancy in women, is routinely treated with combinations of endocrine therapies and radiation or chemotherapy. Nevertheless, half of the patients do not benefit from these treatments because of intrinsic or acquired resistance. 1 Therefore, alternative therapeutic targets in ERa þ breast cancer need to be developed.Work by others has revealed a mammary tumor-promoting effect of prolactin receptor (PrlR) signaling in humans and mice. A meta-analysis of epidemiological data concluded that women in the top quartile for serum prolactin (Prl) concentration have a 60% increased risk of developing ERa þ , but not ERa À , breast cancer, compared with those in the bottom quartile. 2 Consistent with these findings, upregulated PrlR expression and constitutive activation of STAT3 and STAT5 is frequently found in human ERa þ breast cancers. [3][4][5][6]

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Section: Discussionmentioning

confidence: 76%

Dysregulated STAT1-SOCS1 control of JAK2 promotes mammary luminal progenitor cell survival and drives ERα+ tumorigenesis

et al. 2013

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“…Nonetheless, STAT3 activation is a consistent feature in many solid tumors, and it is interesting to note the recent observation documenting the dependence of breast cancer stem-like cells on the JAK2-STAT3 pathway and the association of pathway activation in conjunction with CD44 þ CD24 À stem cell-surface marker expression with disease relapse. 40 These findings suggest there may be distinct solid tumor subpopulations where pathway inhibition is most relevant as well as highlight the need to incorporate additional parameters to identify the appropriate context to use JAK2 inhibitors alone or in combination with other agents.…”

Section: Discussionmentioning

confidence: 95%

Characterization of BMS-911543, a functionally selective small-molecule inhibitor of JAK2

et al. 2011

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We report the characterization of BMS-911543, a potent and selective small-molecule inhibitor of the Janus kinase (JAK) family member, JAK2. Functionally, BMS-911543 displayed potent anti-proliferative and pharmacodynamic (PD) effects in cell lines dependent upon JAK2 signaling, and had little activity in cell types dependent upon other pathways, such as JAK1 and JAK3. BMS-911543 also displayed anti-proliferative responses in colony growth assays using primary progenitor cells isolated from patients with JAK2 V617F -positive myeloproliferative neoplasms (MPNs). Similar to these in vitro observations, BMS-911543 was also highly active in in vivo models of JAK2 signaling, with sustained pathway suppression being observed after a single oral dose. At low dose levels active in JAK2-dependent PD models, no effects were observed in an in vivo model of immunosuppression monitoring antigen-induced IgG and IgM production. Expression profiling of JAK2 V617F -expressing cells treated with diverse JAK2 inhibitors revealed a shared set of transcriptional changes underlying pharmacological effects of JAK2 inhibition, including many STAT1-regulated genes and STAT1 itself. Collectively, our results highlight BMS-911543 as a functionally selective JAK2 inhibitor and support the therapeutic rationale for its further characterization in patients with MPN or in other disorders characterized by constitutively active JAK2 signaling.

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“…The CSCs relies both on cell-autonomous signals and the signals coming from the supportive niche formed by stromal cells within the tumor microenvironment (7,11). Supportive cells include macrophages, fibroblasts, and mesenchymal stem cells that secrete growth factors and cytokines, such as IL6, and create a milieu enabling the cancer cells to acquire and retain stem-like properties (13)(14)(15). Recent reports point to transcriptional regulators, such NF-kB and STAT3, as key elements in the signaling pathways sustaining CSCs in human tumors (16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

EC-70124, a Novel Glycosylated Indolocarbazole Multikinase Inhibitor, Reverts Tumorigenic and Stem Cell Properties in Prostate Cancer by Inhibiting STAT3 and NF-κB

Civenni

Longoni

Costales

et al. 2016

Molecular Cancer Therapeutics

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Cancer stem cells (CSC) contribute to disease progression and treatment failure in prostate cancer because of their intrinsic resistance to current therapies. The transcription factors NF-kB and STAT3 are frequently activated in advanced prostate cancer and sustain expansion of prostate CSCs. EC-70124 is a novel chimeric indolocarbazole compound generated by metabolic engineering of the biosynthetic pathways of glycosylated indolocarbazoles, such as staurosporine and rebeccamycin. In vitro kinome analyses revealed that EC-70124 acted as a multikinase inhibitor with potent activity against IKKb and JAK2. In this study, we show that EC-70124 blocked concomitantly NF-kB and STAT3 in prostate cancer cells and particularly prostate CSCs, which exhibited overactivation of these transcription factors. Phosphorylation of IkB and STAT3 (Tyr705), the immediate targets of IKKb and JAK2, respectively, was rapidly inhibited in vitro by EC-70124 at concentrations that were well below plasma levels in mice. Furthermore, the drug blocked activation of NF-kB and STAT3 reporters and suppressed transcription of their target genes. Treatment with EC-70124 impaired proliferation and colony formation in vitro and delayed development of prostate tumor xenografts. Notably, EC-70124 had profound effects on the prostate CSC subpopulation both in vitro and in vivo. Thus, EC-70124 is a potent inhibitor of the NF-kB and STAT3 signaling pathways and blocked tumor growth and maintenance of prostate CSCs. EC-70124 may provide the basis for developing new therapeutic strategies that combine agents directed to the CSC component and the bulk tumor cell population for treatment of advanced prostate cancer. Mol Cancer Ther; 15(5); 806-18. Ó2016 AACR.

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

Cited by 780 publications

References 63 publications

Dysregulated STAT1-SOCS1 control of JAK2 promotes mammary luminal progenitor cell survival and drives ERα+ tumorigenesis

Dysregulated STAT1-SOCS1 control of JAK2 promotes mammary luminal progenitor cell survival and drives ERα+ tumorigenesis

Characterization of BMS-911543, a functionally selective small-molecule inhibitor of JAK2

EC-70124, a Novel Glycosylated Indolocarbazole Multikinase Inhibitor, Reverts Tumorigenic and Stem Cell Properties in Prostate Cancer by Inhibiting STAT3 and NF-κB

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