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IGF and Insulin Receptor Signaling in Breast Cancer

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Journal of Mammary Gland Biology and Neoplasia Aims and scope Submit manuscript

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.

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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

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Acknowledgements

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

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Authors and Affiliations

  1. Endocrinology, Department of Clinical and Experimental Medicine, University of Catanzaro, 88100, Catanzaro, Italy

    Antonino Belfiore

  2. Endocrinology, Department of Internal Medicine and Medical Specialties, University of Catania, Ospedale Garibaldi-Nesima, 95122, Catania, Italy

    Francesco Frasca

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  1. Antonino Belfiore
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Correspondence to Antonino Belfiore.

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Grant support: This work was partially supported by grants from the AIRC (Associazione Italiana per la Ricerca sul Cancro) and PRIN-MIUR 2005 (Ministero Italiano Università e Ricerca) to A.B.

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Belfiore, A., Frasca, F. IGF and Insulin Receptor Signaling in Breast Cancer. J Mammary Gland Biol Neoplasia 13, 381–406 (2008). https://doi.org/10.1007/s10911-008-9099-z

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