Abstract
Hypoxia is a common feature of solid tumours that promotes invasion and metastatic dissemination. Invadopodia are actin-rich membrane protrusions that direct extracellular matrix proteolysis and facilitate tumour cell invasion. Here, we show that CSRP2, an invadopodial actin bundling protein, is upregulated by hypoxia in various breast cancer cell lines, as well as in pre-clinical and clinical breast tumour specimens. We functionally characterized two hypoxia responsive elements within the proximal promoter of CSRP2 gene which are targeted by hypoxia-inducible factor-1 (HIF-1) and required for promoter transactivation in response to hypoxia. Remarkably, CSRP2 knockdown significantly inhibits hypoxia-stimulated invadopodium formation, ECM degradation and invasion in MDA-MB-231 cells, while CSRP2 forced expression was sufficient to enhance the invasive capacity of HIF-1α-depleted cells under hypoxia. In MCF-7 cells, CSRP2 upregulation was required for hypoxia-induced formation of invadopodium precursors that were unable to promote ECM degradation. Collectively, our data support that CSRP2 is a novel and direct cytoskeletal target of HIF-1 which facilitates hypoxia-induced breast cancer cell invasion by promoting invadopodia formation.
Highlights
Metastasis, i.e. the spread of tumour cells from the primary tumour and subsequent colonization of distant organs, is the most life-threatening aspect of cancer[1]
We provide evidence that Cysteine-rich protein 2 (CSRP2) depletion strongly reduces the ability of hypoxia to enhance invadopodia formation, extracellular matrix (ECM) degradation and invasion in highly invasive breast carcinoma cell lines, such as MDA-MB-231 and mouse 4T1
We assessed the effects of hypoxia on the expression of the pro-invasive and -metastatic invadopodial protein CSRP2 in four breast cancer cell lines, including luminal/epithelial-like MCF-7 and T47D (ER+, PR+), and mesenchymal-like MDA-MB-231 and Hs578T (ER−, PR−, HER2−, claudin-low)
Summary
Metastasis, i.e. the spread of tumour cells from the primary tumour and subsequent colonization of distant organs, is the most life-threatening aspect of cancer[1]. Invadopodia facilitate tumour cell invasion through dense extracellular matrix (ECM) by recruiting transmembrane and secreted metalloproteinases (MMPs) that catalyze ECM component degradation, and creating pores through which mesenchymal tumour cells can migrate[6,7] Both ex vivo and in vivo studies have provided direct evidence of the critical roles of invadopodia during key steps of the metastatic cascade, such as basement membrane breaching, intravasation and extravasation[8,9,10,11,12]. CSRP2 knockdown significantly inhibits invadopodium formation in aggressive breast cancer cells, as well as MMP secretion and 3D matrix invasion It strongly reduces tumour cell dissemination in two mouse models of breast cancer metastasis. Our data point to an important role for CSRP2 in facilitating the pro-invasive and -metastatic effects of hypoxia in breast cancer
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