Immunohistochemical Identification of a Metastasis Modifier Gene (Rrp1b) in Breast Cancer May Help Identify Tumors with High Metastatic Potential
FZ Aly, B Walter Rodriguez, MJ Merino. National Cancer Institute, National Institutes of Health, Bethesda
Background: Breast cancer is the second commonest malignancy in women and most breast cancer related mortality is a consequence of metastasis. A metastasis modifier gene, called signal induced proliferation-associated gene 1 (Sipa-1) has been recently identified in breast tumor cells and its expression has been demonstrated to correlate with increased metastatic capacity. Sipa-1 and a group of related genes constitute the diasporin pathway. Among them, Ribosomal RNA Processing 1 Homolog B (Rrp1b) gene, which directly interacts with the Sipa-1 gene, plays an important role in metastatic predisposition. Over-expression of Rrp1b induces a gene expression signature that predicts survival in in-vitro mammary tumor cells; however, its expression in human breast cancer specimens and its value as a predictive marker of metastatic disease have not been previously investigated in vivo.
Design: Protein expression of Rrp1b gene was evaluated by immunohistochemistry in 54 primary and 17 metastatic breast cancers which included metastases to 11 lymph nodes, 6 lungs, 2 brains and 6 livers. Tissues were scored as positive for Rrpb1 when there was cytoplasmic and/or membranous staining. The staining intensity (weak, moderate or strong) and distribution (diffuse or focal) were noted. The results were correlated with the clinico-pathological data of the patients including prognostic factors.
Results: Overall, positive staining for Rrp1b in the primary breast tumors was seen in 64% of the cases, 67% of the metastatic lymph nodes, 67% of lung metastases and all metastases to the liver and brain. Positive staining was observed in 94% of the infiltrating ductal carcinoma and in none of the infiltrating lobular carcinoma. Strong staining was seen in the metastatic and infiltrating ductal carcinoma, but weak in the ductal carcinoma in-situ cases. Positive Rrp1b staining was seen in 96% of the tumors with positive lymph nodes. Eighty-five per cent of the ER negative cases were positive for Rrp1b (p=0.042). Tumors negative for ER, PR and c-erb2 expressed Rrp1b (p< 0.0001). All tumors >4cm were positive for Rrp1b.
Conclusions: Our results demonstrate for the first time that Rrp1b is indeed expressed in human breast cancers in vivo. Rrp1b expression correlates with clinical stage, hormonal markers and HER-2 amplification. Rrp1b can hence be used as a potential marker of metastatic susceptibility and a possible marker for the development of molecular targets and therapy.
Wednesday, March 24, 2010 1:00 PM
Poster Session VI # 10, Wednesday Afternoon