Abstract
The role of AnxA6 in breast cancer and in particular, the mechanisms underlying its contribution to tumor cell growth and/or motility remain poorly understood. In this study, we established the tumor suppressor function of AnxA6 in triple negative breast cancer (TNBC) cells by showing that loss of AnxA6 is associated with early onset and rapid growth of xenograft TNBC tumors in mice. We also identified the Ca2+ activated RasGRF2 as an effector of AnxA6 mediated TNBC cell growth and motility. Activation of Ca2+ mobilizing oncogenic receptors such as epidermal growth factor receptor (EGFR) in TNBC cells or pharmacological stimulation of Ca2+ influx led to activation, subsequent degradation and altered effector functions of RasGRF2. Inhibition of Ca2+ influx or overexpression of AnxA6 blocked the activation/degradation of RasGRF2. We also show that AnxA6 acts as a scaffold for RasGRF2 and Ras proteins and that its interaction with RasGRF2 is modulated by GTP and/or activation of Ras proteins. Meanwhile, down-regulation of RasGRF2 and treatment of cells with the EGFR-targeted tyrosine kinase inhibitor (TKI) lapatinib strongly attenuated the growth of otherwise EGFR-TKI resistant AnxA6 high TNBC cells. These data not only suggest that AnxA6 modulated Ca2+ influx and effector functions of RasGRF2 underlie at least in part, the AnxA6 mediated TNBC cell growth and/or motility, but also provide a rationale to target Ras-driven TNBC with EGFR targeted therapies in combination with inhibition of RasGRF2.
Highlights
Over the last several years, annexin A6 (AnxA6), a calcium-dependent membrane binding protein, has been shown to play a major role in the differentiation of chondrocytes [1], migration of neural crest cells [2], growth, adhesion and motility of tumor cells [3] and in membrane repair [4, 5]
The role of AnxA6 in breast cancer and in particular, the mechanisms underlying its contribution to tumor cell growth and/or motility remain poorly understood
We identified and validated RasGRF2 as one of the genes that is significantly up-regulated following downregulation of AnxA6 in triple negative breast cancer (TNBC) cells
Summary
Over the last several years, annexin A6 (AnxA6), a calcium-dependent membrane binding protein, has been shown to play a major role in the differentiation of chondrocytes [1], migration of neural crest cells [2], growth, adhesion and motility of tumor cells [3] and in membrane repair [4, 5]. The ability of AnxA6 to regulate the tightly controlled Ca2+ influx is supported by reports demonstrating that AnxA6 modulates the release Ca2+ via interaction with Ca2+ channels such as L-type Ca2+ channels [26], Na+/Ca2+ exchangers [26, 27] and sarcoplasmic reticulum Ca2+-release channels [28]. Some of these channels are known to cluster within membrane lipid rafts [20,21,22], but the role of AnxA6 in the activity of these channels and other Ca2+ activated proteins remains unclear
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