Abstract PR15: Hypoxia induces lapatinib resistance in ErbB2-positive breast cancer cells via regulation of DUSP2
Authors: Karakashev Sergey V. , Mauricio Reginato J. 
Published: August 2014

Abstract
Breast cancer is one of the most common cancers among women. Many factors are associated with this disease including overexpression/amplification of the tyrosine kinase HER2/ErbB2. ErbB2 belongs to the EGFR-family of receptor tyrosine kinases and its overexpression can activate multiple signaling pathways that can promote tumor progression via regulation of cell growth, proliferation, metabolism, and survival. Breast cancer patients with ErbB2 amplifications are currently treated with lapatinib (Tykerb), a small-molecule kinase inhibitor that specifically blocks the active site of ErbB2 to inhibit EGFR/ErbB2 downstream signaling. While lapatinib has displayed clinical efficacy in breast cancer patients, acquired resistance has been reported and the exact mechanism of this resistance is poorly understood.
Hypoxia or low oxygen tension occurs in many breast cancers and is associated with poor patient survival. One of the major players in the cellular response to hypoxia is stabilization of the transcription factor hypoxia inducible factor 1 (HIF-1). HIF-1 is a transcription factor that regulates cell growth, proliferation and survival. As a result, hypoxic tumors often exhibit weak response to different chemotherapeutic agents and poor prognosis.
Here, we show that hypoxia, via HIF-1α, blocks lapatinib-mediated effects on ErbB2-expressing mammary epithelial and ErbB2-positive breast cancer cells. Lapatinib-mediated growth inhibition is reduced under hypoxic conditions (1%O2). Consistent with these results, we find that hypoxia can maintain activation of signaling pathways downstream from ErbB2 including AKT and ERK in the presence of lapatinib. This protective effect depends on HIF-1 expression as cells expressing HIF-1 RNAi no longer are resistant to lapatinib treatment. Moreover, overexpression of stable HIF-1 in ErbB2-expressing cells under normoxic conditions is sufficient to inhibit lapatinib-mediated effects on proliferation and survival and maintain ERK and AKT signaling. One possible mechanism of how HIF-1 may bypass lapatinib-treated inhibition of the ERK pathway is via regulation of dual-specificity phosphatase 2 (DUSP2). DUSP2 is a negative regulator of the ERK pathway and we show that cells exposed to hypoxia contain decreased DUSP2 levels and correlate with increased Erk activation. Indeed, reducing DUSP2 expression alone in ErbB2-positive breast cancer cells is sufficient to reduce lapatinib-mediated effects. Thus, hypoxia, via HIF-1, causes lapatinib resistance in ErbB2-expressing breast cancer cells and suggests that targeting ERK/MAPK pathway in hypoxic breast cancer may increase sensitivity to ErbB2-targeted therapy.
This abstract is also presented as poster C63.
Citation Format: Sergey V. Karakashev, Reginato J. Mauricio. Hypoxia induces lapatinib resistance in ErbB2-positive breast cancer cells via regulation of DUSP2. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr PR15.