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Journal of Mammary Gland Biology and Neoplasia

, Volume 13, Issue 4, pp 381–406 | Cite as

IGF and Insulin Receptor Signaling in Breast Cancer

  • Antonino Belfiore
  • Francesco Frasca
Article

Abstract

Major molecular abnormalities in breast cancer include the deregulation of several components of the IGF system. It is well recognized that the epithelial breast cancer cells commonly overexpress the IGF-I receptor while IGF-II is expressed by the tumor stroma. In view to the fact that the IGF-IR has mitogenic, pro-invasive and anti-apoptotic effects and mediates resistance to a variety of anti-cancer therapies, breast cancer is expected to be a candidate to therapeutic approaches aimed to inhibit the IGF-IR. However, there is increasing awareness that IGF system in cancer undergoes signal diversification by various mechanisms. One of these mechanisms is the aberrant expression of insulin receptor (IR) isoform A (IR-A), which is a high affinity receptor for both insulin and IGF-II, in breast cancer cells. Moreover, overexpression of both IGF-IR and IR-A in breast cancer cells, leads to overexpression of hybrid IR/IGF-IR receptors (HRs) as well. Upon binding to IGF-II, both IR-A and HRs may activate unique signaling patterns, which predominantly mediate proliferative effects. A better understanding of IGF system signal diversification in breast cancer has important implications for cancer prevention measures, which should include control of insulin resistance and associated hyperinsulinemia. Moreover, in addition to the IGF-IR, both IR-A and HRs should be also considered as molecular targets for anti-cancer therapies.

Keywords

Breast cancer Insulin receptor IGF-I receptor IGF-I IGF-II IGF system 

Abbreviations

Akt

Thymoma viral proto-oncogene 1

APS

Associate protein substrate

ATM

Ataxia telangiectasia mutated

BAD

Bcl-2-associated death promoter

Bcl-2

B-cell lymphoma 2

Bcl-XL

Basal cell lymphoma-extra large

Brca1

Breast and ovarian cancer gene 1, early onset

Cbl

Cas-Br-M (murine) ecotropic retroviral transforming sequence

CDK4

Cyclin-dependent kinase 4

DMBA

7,12-Dimethylbenz(a)antracene

4E-BP1

4E-binding protein 1

EGFR

Epidermal growth factor receptor

HER-2

Human epidermal growth factor receptor-2

ER

Estrogen receptor

Erk1/2

Mitogen activated protein kinases

ES

Embryonic stem cells

Fak

Focal adhesion kinase

FKHR

Forkhead in human rabdomyosarcoma

GAB-1

GRB2-associated binding protein 1

GDP

Guanosine diphosphate

GH

Growth hormone

GLUT 4

Glucose transporter protein 4

GTP

Guanosine-5′-triphosphate

HIF1

Hypoxia inducible factor 1

HR-A

IR/IGF-IR hybrid A

HR-B

IR/IGF-IR hybrid B

HRs

IR/IGF-IR hybrid receptors

IGFBP3

Insulin-like growth factor binding protein 3

IGF-IR

IGF-I receptor

IGF-I

Insulin-like growth factor I

IGF-II

Insulin-like growth factor II

IGFs

Insulin-like growth factors

IR

Insulin receptor

IR-A

Insulin receptor isoform A

IR-B

Insulin receptor isoform B

IRR

Insulin receptor-related receptor

JNK

Jun N terminal kinase

LOI

Loss of genomic imprinting

MAD2

Mitotic arrest deficient 2

MMP

Matrix metalloprotease

MMTV

Mouse mammary tumor virus

MAPK

Mitogen activated protein kinase

M6P

Mannose-6-phosphate

M6P/IGF-IIR

Mannose-6-phosphate/IGF-II receptor

mSOS

Son of sevenless protein homolog

mTOR

Mammalian target of rapamycin

OS

Overall survival

PKB

Protein kinase B

PKC

Protein kinase C

PH

Pleckstrin homology

PI3K

Phosphatidylinositol 3-kinase

PKC

Protein kinase C

PKD-1

3-Phosphoinositide-dependent protein kinase 1

PIP3

Phosphatidylinositol (3,4,5)-trisphosphate

Ras

Harvey rat sarcoma virus oncogene 1

RFS

Relapse free survival

S6K1

Ribosomal S6 kinase 1

Src

Rous sarcoma oncogene

SH2

Src-homology 2 domain

Shc

Src/collagen homology proteins

TrkC

Tyrosine kinase C receptor

Notes

Acknowledgements

We thank Prof. Riccardo Vigneri (University of Catania, Italy) for his constant support and advice.

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Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  1. 1.Endocrinology, Department of Clinical and Experimental MedicineUniversity of CatanzaroCatanzaroItaly
  2. 2.Endocrinology, Department of Internal Medicine and Medical SpecialtiesUniversity of CataniaCataniaItaly

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