RCP is a human breast cancer–promoting gene with Ras-activating function

Abstract

Aggressive forms of cancer are often defined by recurrent chromosomal alterations, yet in most cases, the causal or contributing genetic components remain poorly understood. Here, we utilized microarray informatics to identify candidate oncogenes potentially contributing to aggressive breast cancer behavior. We identified the Rab-coupling protein RCP (also known as RAB11FIP1), which is located at a chromosomal region frequently amplified in breast cancer (8p11-12) as a potential candidate. Overexpression of RCP in MCF10A normal human mammary epithelial cells resulted in acquisition of tumorigenic properties such as loss of contact inhibition, growth-factor independence, and anchorage-independent growth. Conversely, knockdown of RCP in human breast cancer cell lines inhibited colony formation, invasion, and migration in vitro and markedly reduced tumor formation and metastasis in mouse xenograft models. Overexpression of RCP enhanced ERK phosphorylation and increased Ras activation in vitro. As these results indicate that RCP is a multifunctional gene frequently amplified in breast cancer that encodes a protein with Ras-activating function, we suggest it has potential importance as a therapeutic target. Furthermore, these studies provide new insight into the emerging role of the Rab family of small G proteins and their interacting partners in carcinogenesis.

Ferroportin and Iron Regulation in Breast Cancer Progression and Prognosis

“…S2), we examined the relationship among hepcidin gene expression, ferroportin gene expression, and disease outcome in breast cancer patients. We selected for this analysis a combined population-based (unselected) cohort in which all patients ( n = 504) had been studied with a microarray platform containing probe sets for both ferroportin and hepcidin (31, 37, 38) (see Materials and Methods). The signal intensity for hepcidin was substantially above the negative control and roughly comparable to that of other genes with roles in breast cancer, such as HER2/neu , ERα , VEGF , BRCA1 , and Ki-67 , confirming the expression of hepcidin in breast tumor tissue (fig.…”

“…The first consists of three population-based cohorts totaling 504 breast cancer cases annotated for clinical follow-up: Uppsala (GSE3494) (35), Stockholm (GSE1456) (31), and Singapore (GSE4922) (37, 38). This data set was used because not all the data sets we previously analyzed for ferroportin included information on hepcidin expression.…”

“…This cohort allowed us to investigate the prognostic interaction between ferroportin and hepcidin in unselected patient populations. The second large combined cohort, unlike the first, consists exclusively of ER + breast cancer cases ( n = 518) derived from both unselected and selected patient populations: Uppsala (GSE3494) (35), Stockholm (GSE1456) (31), Singapore (GSE4922) (37, 38), and Oxford (GSE6532) (54). The Oxford collection is a selected cohort composed of only ER + breast cancer cases treated by adjuvant tamoxifen monotherapy (54).…”

An integrative analysis of colon cancer identifies an essential function for PRPF6 in tumor growth

“…We note that from our analysis of 25 PRPF6-regulated alternatively spliced isoforms, we found several genes with previously described roles in promoting cancer. This includes CAPRIN1 in osteosarcoma growth and metastasis (Sabile et al 2013), RAB11FIP1/RCP in breast cancer growth (Zhang et al 2009), and JAG2 in breast cancer metastasis (Xing et al 2011). Future studies will be needed to further delineate the role of specific ZAK isoforms and other candidate PRPF6-regulated oncogenes in cancer signaling and tumorigenesis.…”

Spatial restriction of receptor tyrosine kinase activity through a polarized endocytic cycle controls border cell migration

“…They have been directly implicated in the migration of cancerous cells and in the formation of metastasis, a cell migration event resembling border cell migration (43)(44)(45). Rab11 effectors are also involved in mammalian cell migration (46)(47)(48). More specifically, PDGF receptor-dependent cell migration has been shown to be regulated by endocytosis in a mammalian cell culture assay (49) and the recycling endosome has been indirectly implicated in the regulation of migration guided by the EGFR (47).…”