Abstract
Cancer cells implement various exocytic routes, modulated by small Rab GTPases, to relay crucial information for fostering growth, invasion and matrix degradation. We investigated the biological role and expression status of Rab27B, a regulator of exosome release, in breast cancer. Rab27B-upregulation in estrogen receptor (ER)-positive breast cancer cells promoted G1/S phase cell cycle transition and increased proliferation, F-actin reorganization and invasion in cell culture and invasive tumor growth and hemorrhagic ascites in a xenograft mouse model. Proteomics of purified Rab27B vesicles and the secretome of Rab27B-expressing breast cancer cells were identified HSP90a as key proinvasive growth regulator. HSP90a secretion occurred in a Rab27B-dependent manner and was required for MMP-2 activation. Endogenous Rab27B mRNA and protein, but not Rab3D and Rab27A mRNA, was associated with lymph node metastasis and differentiation grade in ER-positive breast cancer samples. In conclusion, Rab27B regulates invasive growth and metastasis in ER-positive breast cancer cell lines, and increased expression is associated with poor prognosis in humans. Because of the relationship between Rab27B and cancer progression, elucidating the role of exosomes in metastatic niche formation will be the next step forward in cancer research.
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