by Maria Silvia Giretti, Xiao-Dong Fu, Giovanni De Rosa, Ivana Sarotto, Chiara Baldacci, Silvia Garibaldi, Paolo Mannella, Nicoletta Biglia, Piero Sismondi, Andrea Riccardo Genazzani, Tommaso Simoncini
BackgroundEstrogen is an established enhancer of breast cancer development, but less is known on its effect on local progression or metastasis. We studied the effect of estrogen receptor recruitment on actin cytoskeleton remodeling and breast cancer cell movement and invasion. Moreover, we characterized the signaling steps through which these actions are enacted.
Methodology/Principal FindingsIn estrogen receptor (ER) positive T47-D breast cancer cells ER activation with 17?-estradiol induces rapid and dynamic actin cytoskeleton remodeling with the formation of specialized cell membrane structures like ruffles and pseudopodia. These effects depend on the rapid recruitment of the actin-binding protein moesin. Moesin activation by estradiol depends on the interaction of ER? with the G protein G?13, which results in the recruitment of the small GTPase RhoA and in the subsequent activation of its downstream effector Rho-associated kinase-2 (ROCK-2). ROCK-2 is responsible for moesin phosphorylation. The G?13/RhoA/ROCK/moesin cascade is necessary for the cytoskeletal remodeling and for the enhancement of breast cancer cell horizontal migration and invasion of three-dimensional matrices induced by estrogen. In addition, human samples of normal breast tissue, fibroadenomas and invasive ductal carcinomas show that the expression of wild-type moesin as well as of its active form is deranged in cancers, with increased protein amounts and a loss of association with the cell membrane.
Conclusions/SignificanceThese results provide an original mechanism through which estrogen can facilitate breast cancer local and distant progression, identifying the extra-nuclear G?13/RhoA/ROCK/moesin signaling cascade as a target of ER? in breast cancer cells. This information helps to understand the effects of estrogen on breast cancer metastasis and may provide new targets for therapeutic interventions.
![]() | Pamela B. Morris, MD, Director, Preventive Cardiology, Co-Director, Women’s Heart Care, Medical University of South Carolina, discusses hormone therapy and the risk of cardiovascular disease in women.
References and Resources McGarry KA. Menopause: introduction. Med Health R I. 2008 Mar;91(3):72. Billeci AM, Paciaroni M, Caso V, Agnelli G. Hormone replacement therapy and stroke. Curr Vasc Pharmacol. 2008 Apr;6(2):112-23. Rees M, Stevenson J; British Menopause Society Council. Primary prevention of coronary heart disease in women. Menopause Int. 2008 Mar;14(1):40-5. For more information on this physician visit: Pamela B. Morris, M.D. Views: 2584 Rating: ![]() |
by Albert Salehi, Sandra Meidute Abaraviciene, Javier Jimenez-Feltstrom, Claes-Göran Östenson, Suad Efendic, Ingmar Lundquist
BackgroundA distinctive feature of type 2 diabetes is inability of insulin-secreting ?-cells to properly respond to elevated glucose eventually leading to ?-cell failure. We have hypothesized that an abnormally increased NO production in the pancreatic islets might be an important factor in the pathogenesis of ?-cell dysfunction.
Principal FindingsWe show now that islets of type 2 spontaneous diabetes in GK rats display excessive NO generation associated with abnormal iNOS expression in insulin and glucagon cells, increased ncNOS activity, impaired glucose-stimulated insulin release, glucagon hypersecretion, and impaired glucose-induced glucagon suppression. Pharmacological blockade of islet NO production by the NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME) greatly improved hormone secretion from GK islets suggesting islet NOS activity being an important target to inactivate for amelioration of islet cell function. The incretin hormone GLP-1, which is used in clinical practice suppressed iNOS and ncNOS expression and activity with almost full restoration of insulin release and partial restoration of glucagon release. GLP-1 suppression of iNOS expression was reversed by PKA inhibition but unaffected by the proteasome inhibitor MG132. Injection of glucose plus GLP-1 in the diabetic rats showed that GLP-1 amplified the insulin response but induced a transient increase and then a poor depression of glucagon.
ConclusionThe results suggest that abnormally increased NO production within islet cells is a significant player in the pathogenesis of type 2 diabetes being counteracted by GLP-1 through PKA-dependent, nonproteasomal mechanisms.
by Jae Myoung Suh, Drew Stenesen, John M. Peters, Akiko Inoue, Angela Cade, Jonathan M. Graff
The pursuit of eternal youth has existed for centuries and recent data indicate that fat-storing tissues control lifespan. In a D. melanogaster fat body insertional mutagenic enhancer trap screen designed to isolate genes that control longevity, we identified a regulator of G protein signaling (RGS) domain containing sorting nexin, termed snazarus (sorting nexin lazarus, snz). Flies with insertions into the 5? UTR of snz live up to twice as long as controls. Transgenic expression of UAS-Snz from the snz Gal4 enhancer trap insertion, active in fat metabolic tissues, rescued lifespan extension. Further, the lifespan extension of snz mutants was independent of endosymbiont, e.g., Wolbachia, effects. Notably, old snz mutant flies remain active and fertile indicating that snz mutants have prolonged youthfulness, a goal of aging research. Since mammals have snz-related genes, it is possible that the functions of the snz family may be conserved to humans.