In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 869-869
Abstract:
The basal-like breast cancer (BBC) subtype is generally characterized by positive staining for basal mammary epithelial cytokeratin markers, lack of hormone receptor and HER2 expression, and poor prognosis with currently no approved molecularly-targeted therapies. The oncogenic signaling pathways driving basal-like tumorigenesis, however, are not fully elucidated. In an analysis of phosphoinositide 3-kinase (PI3K) pathway-activating molecular aberrations in 116 unselected breast tumors, we find that three-quarters of cases had a potential oncogenic alteration to PIK3CA, PTEN, HER2, INPP4B, or EGFR, including 97% of estrogen receptor (ER)-negative tumors compared to 65% of ER-positive tumors (P & lt;0.001). Interestingly, nearly all p53 mutant tumors had one or more of these alterations (93%, P=0.001). Loss of PTEN was significantly associated to EGFR overexpression, positivity for the BBC marker cytokeratin 5/14, and the BBC molecular subtype by mRNA gene expression profiling (all P & lt;0.001), informing a potential therapeutic combination targeting the PTEN/PI3K and EGFR pathways in BBC. In BBC cell lines, combination treatment with the EGFR-inhibitor gefitinib plus PI3K-inhibitor LY294002 was synergistic and increased apoptosis. Similarly, in an in vivo BBC xenograft mouse model, gefitinib plus PI3K-inhibitor PWT-458 was more effective than either monotherapy. Our study supports the future clinical evaluation of EGFR and PI3K pathway inhibitors for the treatment of BBC. Citation Format: Lao H. Saal, Qing-Bai She, Sofia K. Gruvberger-Saal, Matthew Maurer, Mervi Jumppanen, Tao Su, Meaghan Dendy, Ying-Ka I. Lau, Lorenzo Memeo, Markus Ringner, Jorma Isola, Hanina Hibshoosh, Neal Rosen, Ramon Parsons. PTEN/PI3K oncogenic pathway profiling informs an in vivo synergistic therapeutic model for basal-like breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 869. doi:10.1158/1538-7445.AM2013-869
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2013-869
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2013
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
