RT Journal Article
SR Electronic
T1 FGFR Signaling Promotes the Growth of Triple-Negative and Basal-Like Breast Cancer Cell Lines Both <em>In Vitro</em> and <em>In Vivo</em>
JF Clinical Cancer Research
JO Clin Cancer Res
FD American Association for Cancer Research
SP 5275
OP 5286
DO 10.1158/1078-0432.CCR-10-2727
VO 17
IS 16
A1 Sharpe, Rachel
A1 Pearson, Alex
A1 Herrera-Abreu, Maria T.
A1 Johnson, Damian
A1 Mackay, Alan
A1 Welti, Jonathan C.
A1 Natrajan, Rachael
A1 Reynolds, Andrew R.
A1 Reis-Filho, Jorge S.
A1 Ashworth, Alan
A1 Turner, Nicholas C.
YR 2011
UL http://clincancerres.aacrjournals.org/content/17/16/5275.abstract
AB Purpose: The oncogenic drivers of triple-negative (TN) and basal-like breast cancers are largely unknown. Substantial evidence now links aberrant signaling by the fibroblast growth factor receptors (FGFR) to the development of multiple cancer types. Here, we examined the role of FGFR signaling in TN breast cancer. Experimental Design: We examined the sensitivity of a panel of 31 breast cancer cell lines to the selective FGFR inhibitor PD173074 and investigated the potential mechanisms underlying sensitivity. Results: TN breast cancer cell lines were more sensitive to PD173074 than comparator cell lines (P = 0.011), with 47% (7/15) of TN cell lines showing significantly reduced growth. The majority of TN cell lines showed only modest sensitivity to FGFR inhibition in two-dimensional growth but were highly sensitive in anchorage-independent conditions. PD173074 inhibited downstream mitogen-activated protein kinase and PI3K–AKT signaling and induced cell-cycle arrest and apoptosis. Basal-like breast cancer cell lines were found to express FGF2 ligand (11/21 positive) and, similarly, 62% of basal-like breast cancers expressed FGF2, as assessed by immunohistochemistry compared with 5% of nonbasal breast cancers (P &lt; 0.0001). RNA interference targeting of FGF2 in basal-like cell lines significantly reduced growth in vitro and reduced down stream signaling, suggesting an autocrine FGF2 signaling loop. Treatment with PD173074 significantly reduced the growth of CAL51 basal-like breast cancer cell line xenografts in vivo. Conclusions: Basal-like breast cancer cell lines, and breast cancers, express autocrine FGF2 and show sensitivity to FGFR inhibitors, identifying a potential novel therapeutic approach for these cancers. Clin Cancer Res; 17(16); 5275–86. ©2011 AACR.