← Back to Search
17β-Estradiol Promotes Breast Cancer Cell Proliferation-Inducing Stromal Cell-Derived Factor-1-Mediated Epidermal Growth Factor Receptor Transactivation: Reversal By Gefitinib Pretreatment
A. Pattarozzi, M. Gatti, F. Barbieri, R. Würth, C. Porcile, G. Lunardi, A. Ratto, R. Favoni, A. Bajetto, A. Ferrari, T. Florio
Published 2008 · Chemistry, Medicine
Save to my Library
Download PDFAnalyze on Scholarcy
The coordinated activity of estrogens and epidermal growth factor receptor (EGFR) family agonists represents the main determinant of breast cancer cell proliferation. Stromal cell-derived factor-1 (SDF-1) enhances extracellular signal-regulated kinases 1 and 2 (ERK1/2) activity via the transactivation of EGFR and 17β-estradiol (E2) induces SDF-1 production to exert autocrine proliferative effects. On this basis, we evaluated whether the inhibition of the tyrosine kinase (TK) activity of EGFR may control different mitogenic stimuli in breast tumors using the EGFR-TK inhibitor gefitinib to antagonize the proliferation induced by E2 in T47D human breast cancer cells. EGF, E2, and SDF-1 induced a dose-dependent T47D cell proliferation, that being nonadditive suggested the activation of common intracellular pathways. Gefitinib treatment inhibited not only the EGF-dependent proliferation and ERK1/2 activation but also the effects of SDF-1 and E2, suggesting that these activities were mediated by EGFR transactivation. Indeed, both SDF-1 and E2 caused EGFR tyrosine phosphorylation. The molecular link between E2 and SDF-1 proliferative effects was identified because 1,1′-(1,4-phenylenebis(methylene))-bis-1,4,8,11-tetraazacyclotetradecane octahydrochloride (AMD3100), a CXCR4 antagonist, inhibited SDF-1- and E2-dependent proliferation and EGFR and ERK1/2 phosphorylation. EGFR transactivation was dependent on c-Src activation. E2 treatment caused a powerful SDF-1 release from T47D cells. Finally, in SKBR3, E2-resistant cells, EGFR was constitutively activated, and AMD3100 reduced EGFR phosphorylation and cell proliferation, whereas HER2-neu was transactivated by SDF-1 in SKBR3 but not in T47D cells. In conclusion, we show that activation of CXCR4 transduces proliferative signals from the E2 receptor to EGFR, whose inhibition is able to revert breast cancer cell proliferation induced by multiple receptor activation.
This paper references
Gefitinib — a novel targeted approach to treating cancer
R. Herbst (2004)
Activation of the MAPK pathway enhances sensitivity of MCF-7 breast cancer cells to the mitogenic effect of estradiol.
W. Yue (2002)
Chemokine Stromal Cell-Derived Factor 1α Induces Proliferation and Growth Hormone Release in GH4C1 Rat Pituitary Adenoma Cell Line through Multiple Intracellular Signals
T. Florio (2006)
Stromal Fibroblasts Present in Invasive Human Breast Carcinomas Promote Tumor Growth and Angiogenesis through Elevated SDF-1/CXCL12 Secretion
A. Orimo (2005)
Chemokines and their receptors in the CNS: expression of CXCL12/SDF-1 and CXCR4 and their role in astrocyte proliferation.
R. Bonavia (2003)
The p160 family coactivators regulate breast cancer cell proliferation and invasion through autocrine/paracrine activity of SDF-1alpha/CXCL12.
H. Kishimoto (2005)
Mechanisms of estrogen action.
S. Nilsson (2001)
Stromal cell derived factor-1: its influence on invasiveness and migration of breast cancer cells in vitro, and its association with prognosis and survival in human breast cancer
H. Kang (2004)
Somatostatin activation of mitogen-activated protein kinase via somatostatin receptor 1 (SSTR1).
T. Florio (1999)
Antitumor effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD-1839 (Iressa), an EGFR-selective tyrosine kinase inhibitor.
F. Ciardiello (2000)
Pleiotropic Coupling of G Protein-coupled Receptors to the Mitogen-activated Protein Kinase Cascade
G. D. Della Rocca (1999)
Elevated Src activity promotes cellular invasion and motility in tamoxifen resistant breast cancer cells
S. Hiscox (2005)
Direct visualization of the human estrogen receptor alpha reveals a role for ligand in the nuclear distribution of the receptor.
H. Htun (1999)
Biologic and therapeutic role of HER2 in cancer
S. Ménard (2003)
Crosstalk between estrogen receptor and growth factor receptor pathways as a cause for endocrine therapy resistance in breast cancer.
C. Osborne (2005)
β-Arrestin Differentially Regulates the Chemokine Receptor CXCR4-mediated Signaling and Receptor Internalization, and This Implicates Multiple Interaction Sites between β-Arrestin and CXCR4*
Z. Cheng (2000)
Akt Activation, but not Extracellular Signal–Regulated Kinase Activation, Is Required for SDF-1α/CXCR4–Mediated Migration of Epitheloid Carcinoma Cells
S. Peng (2005)
CXCR4 knockdown by small interfering RNA abrogates breast tumor growth in vivo
N. Lapteva (2005)
An intracellular multi-effector complex mediates somatostatin receptor 1 activation of phospho-tyrosine phosphatase eta.
S. Arena (2007)
Brain tumors in mice are susceptible to blockade of epidermal growth factor receptor (EGFR) with the oral, specific, EGFR-tyrosine kinase inhibitor ZD1839 (iressa).
A. Heimberger (2002)
The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract
K. Tachibana (1998)
Hyperexpression of mitogen-activated protein kinase in human breast cancer.
V. S. Sivaraman (1997)
Phosphorylation of ERK1/2 mitogen‐activated protein kinase is associated with poor response to anti‐hormonal therapy and decreased patient survival in clinical breast cancer
J. Gee (2001)
Targeting the EGF receptor in ovarian cancer with the tyrosine kinase inhibitor ZD 1839 (‘Iressa’)
J. Sewell (2002)
EGFR and cancer prognosis.
R. Nicholson (2001)
The significance of cancer cell expression of the chemokine receptor CXCR4.
F. Balkwill (2004)
Widespread CXCR4 activation in astrocytomas revealed by phospho-CXCR4-specific antibodies.
B. Woerner (2005)
Epidermal growth factor receptor expression in breast cancer: Association with response to endocrine therapy
Robert I. Nicholson (2004)
Beta-arrestin-dependent formation of beta2 adrenergic receptor-Src protein kinase complexes.
L. Luttrell (1999)
Stromal cell-derived factor 1, a novel target of estrogen receptor action, mediates the mitogenic effects of estradiol in ovarian and breast cancer cells.
J. Hall (2003)
Stromal cell-derived factor-1α (SDF-1α/CXCL12) stimulates ovarian cancer cell growth through the EGF receptor transactivation
C. Porcile (2005)
Involvement of chemokine receptors in breast cancer metastasis
A. Müller (2001)
Stromal cell-derived factor 1alpha stimulates human glioblastoma cell growth through the activation of both extracellular signal-regulated kinases 1/2 and Akt.
S. Barbero (2003)
Direct visualization of EGFR Inhibition Blocks E2/SDF-1-Induced Breast Cancer Growth 201 the human estrogen receptor alpha reveals a role for ligand in the nuclear distribution of the receptor
H Htun (1999)
EGF–ERBB signalling: towards the systems level
A. Citri (2006)
Stromal cell-derived factor-1alpha (SDF-1alpha/CXCL12) stimulates ovarian cancer cell growth through the EGF receptor transactivation.
C. Porcile (2005)
Upregulation of CXCR4 is essential for HER2-mediated tumor metastasis.
Y. Li (2004)
Functions of CXCL12 and CXCR4 in breast cancer.
K. Luker (2006)
Molecular Mechanism of AMD3100 Antagonism in the CXCR4 Receptor
M. Rosenkilde (2004)
Integration of steroid and growth factor pathways in breast cancer: focus on signal transducers and activators of transcription and their potential role in resistance.
C. Silva (2007)
Estrogen-induced activation of mitogen-activated protein kinase requires mobilization of intracellular calcium.
T. Improta-Brears (1999)
Widespread CXCR 4 Activation in Astrocytomas Revealed by Phospho-CXCR 4-Specific Antibodies
B. Woerner (2005)
CXCL-12/stromal cell-derived factor-1alpha transactivates HER2-neu in breast cancer cells by a novel pathway involving Src kinase activation.
N. Cabioğlu (2005)
CXCR4 Regulates Growth of Both Primary and Metastatic Breast Cancer
M. Smith (2004)
CXCR4 and SDF1 expression in human meningiomas: a proliferative role in tumoral meningothelial cells in vitro.
A. Bajetto (2007)
This paper is referenced by
Estrogens in the breast tissue: a systematic review
L. Yaghjyan (2011)
Alternative Translation Initiation of Human Regulators of G-Protein Signaling-2 Yields a Set of Functionally Distinct Proteins
S. Gu (2008)
Disruption of Src function potentiates Chk1-inhibitor-induced apoptosis in human multiple myeloma cells in vitro and in vivo.
Y. Dai (2011)
CXCR4 Expression and Treatment with SDF-1α or Plerixafor Modulate Proliferation and Chemosensitivity of Colon Cancer Cells.
D. Heckmann (2013)
EGFR expression is associated with cytoplasmic staining of CXCR4 and predicts poor prognosis in triple-negative breast carcinomas
Ronghui Li (2017)
Therapeutic potential of estradiol in treating breast cancer
A. Mallick (2019)
Induction of Kruppel-like factor 5 expression by androgens results in increased CXCR4-dependent migration of prostate cancer cells in vitro.
D. E. Frigo (2009)
Multilevel support vector regression analysis to identify condition-specific regulatory networks
L. Chen (2010)
The critical role of SDF-1/CXCR4 axis in cancer and cancer stem cells metastasis
S. Gelmini (2008)
CXCR4 expression in feline mammary carcinoma cells: evidence of a proliferative role for the SDF-1/CXCR4 axis
A. Ferrari (2012)
Computational framework for early detection of breast cancer
A. Yousef (2013)
Canine osteosarcoma cell lines contain stem-like cancer cells: biological and pharmacological characterization.
M. Gatti (2016)
Role of Chemokine Network in the Development and Progression of Ovarian Cancer: A Potential Novel Pharmacological Target
F. Barbieri (2010)
AMD3100 Is a CXCR7 Ligand with Allosteric Agonist Properties
Irina Kalatskaya (2009)
Characterization of oligoadenylate synthetase-1 expression in rat mammary gland and prostate: effects of 17β-estradiol on the regulation of OAS1g in both tissues
C. Maia (2008)
The Chemokine SDF1/CXCL12: A Novel Autocrine/Paracrine Factor Involved In Pituitary Adenoma Development
F. Barbieri (2011)
Anticipatory activation of the unfolded protein response by epidermal growth factor is required for immediate early gene expression and cell proliferation
Liqun Yu (2016)
Oestrogen receptor alpha in pulmonary hypertension
Audrey F. Wright (2015)
Metformin inhibition of neuroblastoma cell proliferation is differently modulated by cell differentiation induced by retinoic acid or overexpression of NDM29 non-coding RNA
Delfina Costa (2014)
Estradiol, TGF-β1 and hypoxia promote breast cancer stemness and EMT-mediated breast cancer migration.
Seongjoon Park (2016)
Vagrant stem cells draft their gene companions.
H. Bonig (2010)
Estrogen-induced SDF-1 production is mediated by estrogen receptor-α in female hearts after acute ischemia and reperfusion.
Chunyan Huang (2011)
Tumor and Stem Cell Biology Cytokine Receptor CXCR 4 Mediates Estrogen-Independent Tumorigenesis , Metastasis , and Resistance to Endocrine Therapy in Human Breast Cancer
L. Rhodes (2011)
Estradiol induces cell proliferation in MCF‑7 mammospheres through HER2/COX‑2.
Chin-Hu Wu (2019)
P-Rex1, a guanine exchange factor that is overexpressed in breast cancer, is a convergence node for ErbB and CXCR4 signaling.
N. Hynes (2011)
Metformin repositioning as antitumoral agent: selective antiproliferative effects in human glioblastoma stem cells, via inhibition of CLIC1-mediated ion current
M. Gritti (2014)
CXCL12 modulation of CXCR4 and CXCR7 activity in human glioblastoma stem-like cells and regulation of the tumor microenvironment
R. Würth (2014)
Cytokine receptor CXCR4 mediates estrogen-independent tumorigenesis, metastasis, and resistance to endocrine therapy in human breast cancer.
L. Rhodes (2011)
Relationship between breast cancer risk factors and mammographic breast density in the Fernald Community Cohort
L. Yaghjyan (2012)
Emerging Targets in Pituitary Adenomas: Role of the CXCL12/CXCR4-R7 System
F. Barbieri (2014)
Gefitinib targets EGFR dimerization and ERK1/2 phosphorylation to inhibit pleural mesothelioma cell proliferation.
R. Favoni (2010)
17β-estradiol induces stearoyl-CoA desaturase-1 expression in estrogen receptor-positive breast cancer cells
Anissa Belkaid (2015)See more