Activation of the FGFR-STAT3 pathway in breast cancer cells induces a hyaluronan-rich microenvironment that licenses tumor formation

Laura R. Bohrer, Polly Chuntova, Lindsey K. Bade, Thomas C. Beadnell, Ronald P. Leon, Nicholas J. Brady, Yungil Ryu, Jodi E. Goldberg, Stephen C. Schmechel, Joe Koopmeiners, James B Mc Carthy, Kaylee Schwertfeger

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Aberrant activation of fibroblast growth factor receptors (FGFR) contributes to breast cancer growth, progression, and therapeutic resistance. Because of the complex nature of the FGF/FGFR axis, and the numerous effects of FGFR activation on tumor cells and the surrounding microenvironment, the specific mechanisms through which aberrant FGFR activity contributes to breast cancer are not completely understood. We show here that FGFR activation induces accumulation of hyaluronan within the extracellular matrix and that blocking hyaluronan synthesis decreases proliferation, migration, and therapeutic resistance. Furthermore, FGFR-mediated hyaluronan accumulation requires activation of the STAT3 pathway, which regulates expression of hyaluronan synthase 2 (HAS2) and subsequent hyaluronan synthesis. Using a novel in vivo model of FGFRdependent tumor growth, we demonstrate that STAT3 inhibition decreases both FGFR-driven tumor growth and hyaluronan levels within the tumor. Finally, our results suggest that combinatorial therapies inhibiting both FGFR activity and hyaluronan synthesis is more effective than targeting either pathway alone and may be a relevant therapeutic approach for breast cancers associated with high levels of FGFR activity. In conclusion, these studies indicate a novel targetable mechanism through which FGFR activation in breast cancer cells induces a protumorigenic microenvironment.

Original languageEnglish (US)
Pages (from-to)374-386
Number of pages13
JournalCancer Research
Volume74
Issue number1
DOIs
StatePublished - Jan 1 2014

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Fibroblast Growth Factor Receptors
Tumor Microenvironment
Hyaluronic Acid
Licensure
Breast Neoplasms
Neoplasms
Growth
Cellular Microenvironment
Therapeutics
Extracellular Matrix

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Activation of the FGFR-STAT3 pathway in breast cancer cells induces a hyaluronan-rich microenvironment that licenses tumor formation. / Bohrer, Laura R.; Chuntova, Polly; Bade, Lindsey K.; Beadnell, Thomas C.; Leon, Ronald P.; Brady, Nicholas J.; Ryu, Yungil; Goldberg, Jodi E.; Schmechel, Stephen C.; Koopmeiners, Joe; Mc Carthy, James B; Schwertfeger, Kaylee.

In: Cancer Research, Vol. 74, No. 1, 01.01.2014, p. 374-386.

Research output: Contribution to journalArticle

Bohrer, Laura R. ; Chuntova, Polly ; Bade, Lindsey K. ; Beadnell, Thomas C. ; Leon, Ronald P. ; Brady, Nicholas J. ; Ryu, Yungil ; Goldberg, Jodi E. ; Schmechel, Stephen C. ; Koopmeiners, Joe ; Mc Carthy, James B ; Schwertfeger, Kaylee. / Activation of the FGFR-STAT3 pathway in breast cancer cells induces a hyaluronan-rich microenvironment that licenses tumor formation. In: Cancer Research. 2014 ; Vol. 74, No. 1. pp. 374-386.
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abstract = "Aberrant activation of fibroblast growth factor receptors (FGFR) contributes to breast cancer growth, progression, and therapeutic resistance. Because of the complex nature of the FGF/FGFR axis, and the numerous effects of FGFR activation on tumor cells and the surrounding microenvironment, the specific mechanisms through which aberrant FGFR activity contributes to breast cancer are not completely understood. We show here that FGFR activation induces accumulation of hyaluronan within the extracellular matrix and that blocking hyaluronan synthesis decreases proliferation, migration, and therapeutic resistance. Furthermore, FGFR-mediated hyaluronan accumulation requires activation of the STAT3 pathway, which regulates expression of hyaluronan synthase 2 (HAS2) and subsequent hyaluronan synthesis. Using a novel in vivo model of FGFRdependent tumor growth, we demonstrate that STAT3 inhibition decreases both FGFR-driven tumor growth and hyaluronan levels within the tumor. Finally, our results suggest that combinatorial therapies inhibiting both FGFR activity and hyaluronan synthesis is more effective than targeting either pathway alone and may be a relevant therapeutic approach for breast cancers associated with high levels of FGFR activity. In conclusion, these studies indicate a novel targetable mechanism through which FGFR activation in breast cancer cells induces a protumorigenic microenvironment.",
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