Enhanced Expression of Rab27A Gene by Breast Cancer Cells Promoting Invasiveness and the Metastasis Potential by Secretion of Insulin-Like Growth Factor-II

Abstract

In addition to the functions of transporting melanosome in melanocytes and releasing contents of lytic granules in CTLs, Rab27A was recently shown to be involved in exocytosis of insulin and chromaffin granules in endocrine cells; it was also reported to be expressed in an exceptionally broad range of specialized secretory cells. As autocrine and paracrine cytokines are essential for invasion and metastasis in some solid tumors, blocking them may be an effective strategy to prevent tumor dissemination. In the present study, we show that Rab27A is associated with invasive and metastatic potentials of human breast cancer cells. The overexpression of Rab27A protein redistributed the cell cycle and increased the invasive and metastatic abilities in breast cancer cells both in vitro and in vivo. We also certified that Rab27A conferred the invasive and metastatic phenotypes on breast cancer cells by promoting the secretion of insulin-like growth factor-II (IGF-II), which regulates the expression of p16, vascular endothelial growth factor, matrix metalloproteinase-9, cathepsin D, cyclin D1, and urokinase-type plasminogen activator. These data provide functional evidence that Rab27A acts as a novel mediator of invasion and metastasis promotion in human breast cancer cells, at least in part, through regulating the secretion of IGF-II, suggesting that synergistic suppression of Rab27A and IGF-II activities holds a promise for preventing breast cancer invasion and metastasis.

Inhibition of EGFR pathway signaling and the metastatic potential of breast cancer cells by PA-MSHA mediated by type 1 fimbriae via a mannose-dependent manner

“…Cell cycle and apoptotic analyses were performed by flow cytometry (FCM) as previously described using an FACScalibur system (Wang et al, 2008). Apoptotic cells were analyzed by quadrant statistics of the propidium iodidenegative and annexin V-positive cells.…”

The secretory small GTPase Rab27B as a marker for breast cancer progression

“…Rab27B exhibits a peripheral distribution in MCF-7 cells and a cytoplasmic pattern in MDA-MB-231 cells; Rab27A is localized at the cell periphery in MDA-MB-231 cells and in the cytoplasm in MCF-7 cells. Both we and Wang et al obtained the cell lines directly from ATCC [3,15]. Differences in Rab27 expression and localization could be attributed to failure of Rab27B-specific primers in the semi-quantitative PCR assay or the lack of specificity of the Rab27A antibody used by Wang and coworkers.…”

“…Rab27A mRNA and protein levels increased with the in vitro invasive potential of the breast cancer cells studied [15]. Using semi-quantitative real-time RT-PCR and primers and PCR conditions that were not specified, Wang et al found no Rab27B mRNA expression in non-invasive, ER-positive MCF-7 cells, and in invasive ER-negative MDA-MB-231 cells [15]. In contrast, we observed both Rab27A and Rab27B expression in these cells, employing quantitative real-time PCR and Western blotting (Fig.…”

“…Interestingly, Wang et al (2008) reported Rab27A-dependent invasion and xenograft metastasis of ER-negative, already invasive, MDA-MB-231 and MDA-MB-435 breast cancer cells. Rab27A mRNA and protein levels increased with the in vitro invasive potential of the breast cancer cells studied [15]. Using semi-quantitative real-time RT-PCR and primers and PCR conditions that were not specified, Wang et al found no Rab27B mRNA expression in non-invasive, ER-positive MCF-7 cells, and in invasive ER-negative MDA-MB-231 cells [15].…”

Tumor Suppressor Gene p16/INK4A/CDKN2A and Its Role in Cell Cycle Exit, Differentiation, and Determination of Cell Fate

“…Rab27A is also linked with human genetic diseases (Seabra et al, 2002). Rab27A is associated with invasive and metastatic breast cancer, which is facilitated by down-regulation of p16 and up-regulation of cyclinD1 (Wang et al, 2008). Concomitant overexpression of p16 and p73 has oncogenic potential and affects the development and growth of breast carcinomas (Garcia et al, 2004).…”