Abstract
Recurrent metastasis is a major fatal cause of breast cancer. Regretfully, the driving force and the molecular beneath have not been fully illustrated yet. In this study, a cohort of breast cancer patients with locoregional metastasis was recruited. For them, we collected the matched samples of the primary tumor and metastatic tumor, and then we determined the mutation profiles with whole-exome sequencing (WES). On basis of the profiles, we identified a list of deleterious variants in eight susceptible genes. Of them, filamin A (FLNA) was considered a potential driver gene of metastasis, and its low expression could enhance 5 years’ relapse survival rate by 15%. To prove the finding, we constructed a stable FLNA knockout tumor cell line, which manifested that the cell abilities of proliferation, migration, and invasion were significantly weakened in response to the gene knockout. Subsequently, xenograft mouse experiments further proved that FLNA knockout could inhibit local or distal metastasis. Putting all the results together, we consolidated that FLNA could be a potential driver gene to metastasis of breast cancer, in particular triple-negative breast cancer. Additional experiments also suggested that FLNA might intervene in metastasis via the regulation of MMP-1 expression. In summary, this study demonstrates that FLNA may play as a positive regulator in cancer proliferation and recurrence. It provides new insight into breast cancer metastasis and suggests a potential new therapeutic target for breast cancer therapy.
Highlights
Breast cancer has become the most common cancer and the main cause of cancer death in women
The analyses were made based on an open assumption of the following: 1) the cohort patients may have different genetic backgrounds of metastasis (Table 1), 2) the metastatic driver gene mutations could be harmful to the cells, and 3) the deleteriousness of gene mutations would be a benefit to metastasis
These deleterious mutations were distributed on all chromosomes except the Y chromosome, and the majority of them occurred in protein-coding regions (Figure 1B)
Summary
Breast cancer has become the most common cancer and the main cause of cancer death in women. The 5-year survival rate of breast cancer is increasing year by year, drug resistance, recurrence, and metastasis are still urgent problems in the treatment of cancer. The occurrence and development of breast cancer are the results of the interaction of genes and environment, and the effect of the environment can be manifested through genetic or epigenetic changes [8]. Abdullah et al found that inhibition of PTEN can promote the activation of the PI3K/Akt pathway and further control the proliferation and development of breast cancer stem cells (CSCs) [14]. We collected nine pairs of primary and recurrent tumors of breast cancer patients, determined the mutation profiles with whole-exome sequencing (WES), identified potential driver genes, and further validated them with both cells and animal experiments. We intended to provide new insights into breast cancer metastasis and suggest potential new therapeutic targets for precise breast cancer therapy
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