Abstract
ERBB2/HER2 belongs to the EGFR-family of receptor tyrosine kinases and its overexpression can promote tumor progression. Breast cancer patients with ERBB2 amplifications are currently treated with lapatinib, a small-molecule kinase inhibitor that specifically blocks EGFR/ERBB2 signaling. Here, we show that hypoxia, via HIF-1, induces resistance to lapatinib-mediated effects in ERBB2-expressing mammary epithelial and ERBB2-positive breast cancer cells. Lapatinib-mediated growth inhibition and apoptosis in three-dimensional (3D) cultures are decreased under hypoxic conditions. Hypoxia can maintain activation of signaling pathways downstream from ERBB2 including AKT and ERK in the presence of lapatinib. HIF-1 is both required and sufficient to induce lapatinib resistance as overexpression of stable HIF-1 in ERBB2-expressing cells blocks lapatinib-mediated effects and maintains ERBB2-downstream signaling under normoxic conditions. Under hypoxia, activation of ERK signaling is required for lapatinib resistance as treatment with MEK inhibitor trametinib reverses hypoxia-mediated lapatinib resistance. HIF-1 can bypass the lapatinib-treated inhibition of the ERK pathway via inhibition of the dual-specificity phosphatase 2 (DUSP2). Indeed, overexpression of DUSP2 in ErbB2-positve breast cancer cells reverses hypoxia-mediated lapatinib resistance. Thus, our results provide rationale for therapeutic evaluation of the treatment of hypoxic ERBB2 expressing breast tumors with a combination of lapatinib and MEK inhibitors.
Highlights
Despite significant progress in treatment and diagnostics, breast cancer remains the second most deadly cancer among women in the developed world [1]
Since HIF-1α expression is associated with poor clinical outcome in breast cancer patients [33] and we show that hypoxia via HIF-1α reduces dual-specificity phosphatase 2 (DUSP2) expression, www.impactjournals.com/oncotarget we interrogated whether DUSP2 expression may be associate with poor clinical outcome in breast cancer patients
We demonstrate for the first time that hypoxia promotes lapatinib resistance in ERBB2-positive breast cancer cells through activation of the MEK-extracellular signal-regulated kinase (ERK) pathway in a Hypoxia inducible factor 1 (HIF-1)-dependent manner via regulation of DUSP2 (Figure 6C)
Summary
Despite significant progress in treatment and diagnostics, breast cancer remains the second most deadly cancer among women in the developed world [1]. Breast cancer is a highly heterogeneous disease, classified by stage, size, morphology and the presence of receptors such as estrogen receptor, progesterone receptor or ERBB2/HER2. ERBB2 is a receptor tyrosine kinase that is overexpressed in over 30% of breast tumors [2, 3]. This oncogene belongs to the EGFR receptor family and plays an important role in EGFR pathway signaling. This pathway is triggered by EGFR activation via binding to its ligand EGF resulting in activation of EGFR/ERBB2 downstream target proteins including the serine/threonine kinase AKT and extracellular signal-regulated kinase (ERK). ERK kinase regulates multiple downstream targets involved in regulation of cell proliferation and survival and the ERK pathway is deregulated in many cancers
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