About 25% of the newly diagnosed cancers in women in 2020 were breast malignancies (https://gco.iarc.fr/today). Although substantial advance has been achieved to treat this disease in the last decades, once breast cancer spreads to other parts of the body and metastasizes, life quality and expectancy decreases substantially. In order to colonize distant tissues, breast cancer cells need to migrate and invade the surrounding tissue, making these processes a distinctive trait of malignancy and attractive targets for drug development.
With this in mind, our main aim was to find genes with putative functions as positive regulators of tumor cell migration and invasion. In order to do so, we performed a loss-of-function genetic screen, using a pooled-shRNA library targeting Ubiquitin/Proteasome System-related genes. Why ubiquitination? Because this is a post-translational modification that regulates the fate and function of many proteins and shows potential as a point of therapeutic intervention in cancer. We used a well-characterized highly invasive breast cancer cell line in order to perform our migration screen, and selected cells that had a decreased migratory capability as a consequence of the shRNAs expression. We reasoned that under those circumstances, shRNAs that blocked the expression of activators of migration would get enriched in our functional selection. Genes targeted by those enriched shRNAs would be our candidate targets.
After sequencing and quantifying the shRNAs, we found that about half of the candidate genes had already been described in their relation to tumor cells migration, invasion, or metastasis, serving as a proof of principle that we were on the right track.
We then decided to focus our attention on the deubiquitinating enzyme USP19, as there were no previous reports relating its functions to the regulation of breast cancer cells migration or invasion.
Firstly, we performed a series of in vitro experiments which showed that manipulating USP19 expression affected migration, invasion, growth in three dimensions, but not proliferation in two dimensions. These results were even more pronounced when we performed in vivo experiments: USP19 downregulation reduced tumorigenicity and tumor growth, as well as lungs colonization, and its sole overexpression induced tumor growth in cells which do not usually form tumors unless exogenously stimulated. Using an in silico approach, we realized that USP19 expression was correlated with the activation of the Wnt pathway. Therefore, we studied an already-known substrate of USP19, LRP6 (a Wnt pathway co-receptor), and demonstrated that USP19 mechanism of action in the regulation of migration involved this latter.
Very excited about our findings, we decided to perform a retrospective study of early breast cancer patients. Our results indicated that USP19 overexpression is a surrogate prognostic marker of distant relapse in patients with early breast cancer.
For all the reasons expressed before, we concluded that USP19 is relevant for the regulation of breast cancer cell dissemination and its expression levels correlate with high risk of metastases development and could therefore represent a novel target for the management of breast cancer metastatic disease, in particular when LRP6 expression is relevant for determining patients’ outcome.
This work shows how mitochondria chaperone GRP75 regulates the stability of SIX1, a transcription factor for embryonic development and cancer progression. Our findings provide important insights into the protein degradation mechanism as well as a novel avenue for prostate cancer therapy.
Besides eradicating tumour cells with deficiencies for homologous recombination, PARP inhibitors can induce the activation of CAFs within the TME via NF-κB/CCL5 pathway. CCL5 blockade blunts the reprogramming of CAFs conditioned by PARP inhibitors and potentiates PARP inhibitors.
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