Angiogenin Regulation by Estradiol in Breast Tissue: Tamoxifen Inhibits Angiogenin Nuclear Translocation and Antiangiogenin Therapy Reduces Breast Cancer Growth In vivo

Abstract

Purpose: Angiogenin, a 14.2-kDa polypeptide member of the RNase A superfamily, has potent angiogenic effects. Nuclear accumulation of angiogenin is essential for its angiogenic activity. Increased angiogenin expression has been associated with the transition of normal breast tissue into invasive breast carcinoma. In this article, we investigated whether estradiol (E 2 ) affected angiogenin in breast tissue.Experimental Design: We used microdialysis for sampling of extracellular angiogenin in vivo. In vitro cultures of whole normal breast tissue, breast cancer cells, and endothelial cells were used.Results: We show that extracellular angiogenin correlated significantly with E 2 in normal human breast tissue in vivo and that exposure of normal breast tissue biopsies to E 2 stimulated angiogenin secretion. In breast cancer patients, the in vivo angiogenin levels were significantly higher in tumors compared with the adjacent normal breast tissue. In estrogen receptor-positive breast cancer cells, E 2 increased and tamoxifen decreased angiogenin secretion. Moreover, E 2 -induced angiogenin derived from cancer cells significantly increased endothelial cell proliferation. Tamoxifen reversed this increase as well as inhibited nuclear translocation of angiogenin. In vivo, in experimental breast cancer, tamoxifen decreased angiogenin levels and decreased angiogenesis. Additionally, treating tumor-bearing mice with an antiangiogenin antibody resulted in tumor stasis, suggesting a role for angiogenin in estrogen-dependent breast cancer growth.Conclusion: Our results suggest previously unknown mechanisms by which estrogen and antiestrogen regulate angiogenesis in normal human breast tissue and breast cancer. This may be important for estrogendriven breast cancer progression and a molecular target for therapeutic interventions.

Estradiol Promotes Breast Cancer Cell Migration via Recruitment and Activation of Neutrophils

“…#P000127, 10-mm; refs. 25,26). Catheters, connected to a pump (CMA 107; CMA Microdialysis AB), were perfused with 154 mmol/liter NaCl and 60 g/liter hydroxyethyl starch (Voluven; Fresenius Kabi AB; cat.…”

Dense breast tissue in postmenopausal women is associated with a pro-inflammatory microenvironment in vivo

“…One microdialysis catheter was placed in the upper lateral quadrant of the left breast and directed toward the nipple as previously described 5,7,8,34,[43][44][45][46][47][48] and one reference catheter was placed in abdominal subcutaneous fat. Microdialysis catheters (71/M Dialysis AB, Stockholm, Sweden), which consists of a tubular dialysis membrane (length 20 mm, diameter 0.52 mm, and 100,000 atomic mass cut-off) glued to the end of a double-lumen tube (80 mm long £ 0.8 mm in diameter), were inserted via a splitable introducer (M Dialysis AB), connected to a microinfusion pump (M Dialysis AB) and perfused with NaCl 154 mmol/L and hydroxyethyl starch 60 g/L (Voluven Ò , Fresenius Kabi, Uppsala, Sweden), at a perfusion rate of 0.5 mL/min.…”

Ecosystems of invasion and metastasis in mammary morphogenesis and cancer

“…Nuclear accumulation of angiogenin, a member of the RNase superfamily, is essential for angiogenic activity and its increased expression may transform normal breast tissue into invasive carcinoma. Angiogenin is stimulated by E2 and counteracted by the ER antagonist tamoxifen (Nilsson et al, 2010). Using breast cancer cell lines, Harfouche et al (2011) showed a negative correlation between the expression of angiopoietin -1, a ligand for the endothelial tyrosine kinase receptor Tie-2, and levels of ERa and a positive correlation with angiogenesis.…”