ETD

Archivio digitale delle tesi discusse presso l'Università di Pisa

Tesi etd-03262012-110248


Tipo di tesi
Tesi di dottorato di ricerca
Autore
GOPAL, SANTHOSH
URN
etd-03262012-110248
Titolo
RAPID SIGNALING OF CONVENTIONAL AND UNCONVENTIONAL ESTROGEN RECEPTORS TO THE ACTIN CYTOSKELETON AND CELL MOVEMENT
Settore scientifico disciplinare
MED/13
Corso di studi
SCIENZE ENDOCRINE E METABOLICHE
Relatori
tutor Prof. Simoncini, Tommaso
Parole chiave
  • G protein coupled estrogen receptor
  • estrogen
  • estrogen receptors
  • actin cytoskeleton
Data inizio appello
04/04/2012
Consultabilità
Completa
Riassunto
Female sex steroid estrogen is the fundamental regulator of normal breast development. In addition
to this, clinical data showed that aromatase inhibitors reduces early distant metastasis and
improves disease-free survival indicating that estrogen may facilitate the progression of breast
cancer. Cell migration is required for cancer spread, invasion, and metastasis. Cell migration
requires the integration of events that induce changes in cell structure such as protrusion,
polarization and traction toward the direction of migration. These actions are driven by actin
remodeling. These events are dependent on the rapid activation of FAK and Moesin, a member of
ERM (Ezrin, Radixin and Moesin) family. However, the mechanistic basis of estrogens on
endothelial and breast tumor cell motility or invasion remains unclear. The main focus of this
thesis is to study the role of conventional and unconventional estrogen receptors in cell movement
in different cell settings. First we used human umbilical vein endothelial cells and ER negative
MDA MB468 cells to study the mechanistic basis of cell movement in non cancerous human vein
endothelial cells and breast cancer MDA-MB 468 cells, these two cells enable us to provide
insights into how steroids induces metastasis in breast cancer cells. The first part of my thesis
focuses on exploring the regulatory actions of estrogen on PAI-1 in human endothelial cells and to
characterize the signaling steps through which these actions are enacted. Here we have shown that
estrogen through various signaling intermediates from membrane to nucleus, to induce the
expression of PAI-1. Our lab have shown previously that estrogen is the powerful modulator of
cell movement in ER positive T47D breast cancer cells. The interesting point is that, PAI-1 besides
being important player in fibrinolysis, also demonstrated to have other roles such as actin
remodeling. Actin remodeling is the crucial event. The fundamental goal of this second part of
Thesis are to explore the dynamics and regulatory controls of actin based processes in an effort to further understand the molecular events governing invasion and cell movement. Within this
context, the work presented here focuses on the role of unconventional estrogen receptors such as
G-Protein Coupled Estrogen Receptor (GPER) in ER negative breast tumor MDA MB468 cell
line. Previous studies have shown with debate that, apart from endogenous ER receptors, GPER is
an unconventional estrogen receptor which is used by sex steroids such as estrogen. Previous
studies have also shown that estrogen exerts trace effect in the cells without ER, so we
hypothesized that, this trace effect could be the presence of unconventional GPER in ER negative
breast cancer cells. These findings described in this thesis provide new mechanisms of action of
estrogens through conventional and unconventional estrogen receptors to the actin cytoskeleton
and cell movement, which may be important for vascular function and heamostasis in endothelial
cells and invasion and metastasis in breast cancer cells.
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