Ju Young Ahn

Introduction. Human breast cancer is a highly prevalent disease and it is estimated that 2.1 million women were diagnosed with breast cancer in 2018 globally.¹ Human breast cancer has a microenvironment with reduced O₂ availability or hypoxia.⁵ In this hypoxic condition, HIF has been reported to be the master regulator that mediates intra-tumoral hypoxia and breast tumor metastasis.⁵ Therefore, many research studies have investigated the pathway of HIF-dependent activation as a novel therapeutic drug target or a potential biomarker that would be beneficial to breast cancer patients. Methods.  Hypoxia is hypothesized to up-regulate CSRP2, which is the “invadopodial actin bundling protein,” and this protein promotes tumor cell invasion.⁶ HIF-1α knockdown of a mouse model caused inhibition of CSRP2 up-regulation in hypoxia-induced cells, suggesting that HIF-1 targets CSRP2 as a downstream effect.⁶ Moreover, another study successfully generated hypoxia fate-mapping transgenic mouse.⁴ In these mice, tumor cells which are exposed to hypoxia irreversibly express GFP signals, which can be tracked using imaging analysis and FACs to further investigate post-hypoxic tumor cells.⁴ Results. Studies have found that HIF-1 targeted the promoter of CSRP2 gene, and forced expression of CSRP2 gene in HIF-1α-depleted cells caused greater invasive capacity of tumor cells.⁶ In the hypoxia fate-mapping transgenic mouse model, post-hypoxic tumor cells were observed to show ROS-resistant phenotype, which allowed them to establish metastasis in these mice.⁴ Moreover, RNA-sequence analysis revealed up-regulation of 9 genes, which are related to HIF.⁴ Potential therapeutic targets related to HIF have also been explored. Parkin, an E3 ubiquitin ligase was investigated as a potential target to ubiquitinate HIF-1a and cause proteasomal degradation.⁷ Moreover, it was shown that tumour-associated macrophages (TAMs) release extracellular vesicles (EVs) with long non-coding RNAs (lncRNAs) that stabilize HIF-1a.⁸ Conclusions. Molecular mechanism of HIF dependent pathway was investigated and showed that CSRP2 could be a novel target to inhibit HIF-1 facilitated tumor invasion by hindering the formation of invadopodia.⁶ Also, a novel hypoxia fate-mapping transgenic mouse model system can be utilized in the future to assess chemotherapeutic effects in post-hypoxic metastatic cells.⁴ Therapeutic targets related to HIF were also explored as Parkin was able to promote ubiquitination and degradation of HIF-1α, inhibiting breast cancer metastasis.⁷ Lastly, EVs, released from TAMs, contained HIF-1α-stabilizing long noncoding RNA (HISLA) which inhibited HIF-1α degradation. As a result, identification of HISLA could potentially become a prognostic tool to determine chemoresistance and survival of breast cancer patients.⁸

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