Abstract 3463: Targeting Hedgehog pathway and EGFR signaling to overcome endocrine resistance
Authors: Rudolph Mark A. , Sizemore Stephen , Lu Yuanzhi , Teng Kun-yu , Gonos Alec , Ramaswamy Bhuvaneswari , Majumder Sarmila 
Published: August 2015

Rationale: Endocrine therapy is the cornerstone in the management of patients with estrogen receptor positive (ER+) breast cancer (BC). While endocrine therapy is very effective, 30-40% of patients will develop resistance. Our lab has previously shown that the PI3K/AKT pathway activates the Sonic Hedgehog pathway, stabilizing the activated transcription factor, GLI-1, and contributing to the development of endocrine resistance (Ramaswamy B et al: Can Res:August 2012). The purpose of our current study is to elucidate how GLI-1 modulates its target genes that contribute to endocrine-resistance.

Methodology: Ectopic expression of GLI-1 in MCF7 cells was followed by microarray gene expression analysis. The GLI-1 signature characterized by differential expression of several BC associated genes was next validated in vitro using real-time PCR. We next utilized the Hatzis data set to determine whether these signature genes correlated with GLI-1 expression in BC patients and whether expression of these genes could be predictive of metastatic recurrence.

Results: Several known GLI-1 targets and novel genes were found to be differentially expressed in GLI-1 overexpressing MCF-7 cells. The expression profile of the majority of these genes followed a similar pattern in the endocrine resistant cell lines, as determined by real-time PCR. Our analysis with the Hatzis data set revealed that several genes were positively correlated with GLI-1 expression (ATM, BRCAI, EGFR, ESR2, SERPINE1, SNAI1, IL6) and several genes were negatively correlated with GLI-1 expression (IGF1R, MUC1, PGR, SLC-39A6, THBS1, XBP1). Of these signature genes, co-expression of GLI-1 & EGFR and GLI-1 & SNAI1 were predictive of metastatic recurrence in the luminal A subtype only. Western blot analysis showed an increase in total EGFR and EGFR phosphorylation upon GLI-1 overexpression in MCF7 cells suggesting cross-talk between Hedgehog pathway and EGFR signaling.

Conclusions: The Luminal A breast cancer subtype is the most common molecular subtype of breast cancer. Although associated with good prognosis, many patients with this subtype ultimately have a recurrence. Interestingly we observed that combined expression of EGFR and GLI-1 was predictive of metastatic recurrence in patients with the luminal A subtype. Prior trials of targeting EGFR with endocrine therapy have not been very successful. We propose that dual targeting of EGFR and hedgehog pathways could improve clinical outcomes of ER+ BC and warrants further investigation.

Citation Format: Mark A. Rudolph, Stephen Sizemore, Yuanzhi Lu, Kun-yu Teng, Alec Gonos, Bhuvaneswari Ramaswamy, Sarmila Majumder. Targeting Hedgehog pathway and EGFR signaling to overcome endocrine resistance. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3463. doi:10.1158/1538-7445.AM2015-3463