Development of metastases in mice induced by plasma sample collected during radiotherapy in patient with triple-negative breast cancer: Role of Rab4A

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ABSTRACT The relapse rate in early-stage triple-negative breast cancer (TNBC) is significantly higher than in other breast cancer subtypes. This study assessed the relevance to target RAB4A to prevent the development of metastases that occur after treatment. The ability of cancer cells to invade peritumoral tissue is associated with the expression of membrane-type matrix metalloproteinase-1 on their surface, which is regulated by RAB4A. When RAB4A was downregulated using shRNA in the TNBC cells D2A1 and MDA-MB-231, a significant reduction in the proteolytic activity of MT1-MMP and the invasion capacity of these TNBC cells were measured. Plasma samples from an early-stage TNBC patient, who developed metastases six months after treatment, were collected before radiotherapy and after the fourth radiation dose. Compared to the plasma collected before radiotherapy, the plasma collected during the treatment significantly enhanced the invasiveness of the TNBC cells, as assessed with Boyden chambers. The development of lung metastases was also stimulated when the D2A1 cells were preincubated with this plasma before their i.v. injection in female Balb/c mice. Importantly, these adverse effects of plasma collected during radiotherapy were significantly blocked by downregulating RAB4A. These results highlight the relevance of developing RAB4A inhibitors to prevent the development of metastases occurring after treatment in TNBC patients.

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