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Jak2/Stat5 Signaling in Mammogenesis, Breast Cancer Initiation and Progression

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

Abstract

During normal mammary gland development, the tyrosine kinase Jak2 and its main substrate, the signal transducer and activator of transcription-5 (Stat5), are critical for the growth and differentiation of alveolar progenitors as well as the survival of secretory mammary epithelial cells. Genetic studies in mouse models support a role for the Stat5 transcription factor as a proto-oncogene in mammary tumor initiation. On the other hand, the analysis of nuclear Stat5 in human breast malignancies suggests a role of the Jak2/Stat5 pathway in the restriction of the metastatic potential of neoplastic mammary epithelial cells. Following an overview on the function of the Jak2/Stat5 pathway during normal mammary gland development, this review discusses recently published observations on human breast cancers as well as experimental evidence from genetically engineered mice that propose a dual role of Jak2/Stat5 signaling in breast cancer initiation and progression. Future studies to further test the concept of contrasting effects of Jak2/Stat5 pathway on breast cancer initiation and metastatic progression are proposed.

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Abbreviations

Akt:

thymoma viral proto-oncogene 1

AP-1:

adaptor protein 1

Bcl-x:

B-cell leukemia gene 2-like 1 gene

Brca1:

breast and ovarian cancer gene 1, early onset

Cish:

cytokine inducible SH2-containing protein

Cre:

site-specific recombinase in bacteriophage P1 (catalyses recombination between loxP sites)

EGF:

epidermal growth factor

ER:

estrogen receptor

ErbB2–4:

epidermal growth factor receptors 2–4

Erk1/2:

mitogen activated protein kinases

Fak:

focal adhesion kinase

floxed:

flanked by loxP sites

GH:

growth hormone

GM-CSF-R:

colony stimulating factor 2 receptor, alpha, low-affinity (granulocyte-macrophage)

gp130:

interleukin 6 signal transducer

Her2/Neu:

ErbB2; member of the epidermal growth factor receptor family

IGF-2:

insulin-like growth factor 2

IL-3R:

interleukin 3 receptor

Jak2:

Janus kinase 2

loxP:

locus of crossing (X-ing) over

MAPK:

mitogen activated protein kinase

MECs:

mammary epithelial cells

MMTV:

mouse mammary tumor virus

Myc:

myelocytomatosis oncogene

PI-MECs:

parity-induced mammary epithelial cells

PI3K:

phosphatidylinositol 3-kinase

PIAS:

protein inhibitor of activated signal transducers and activators of transcription

PRL:

prolactin

PRLR:

prolactin receptor

PKC:

protein kinase C

Ras:

Harvey rat sarcoma virus oncogene 1

SOCS:

suppressor of cytokine signaling

Src:

Rous sarcoma oncogene

Stat5:

signal transducer and activatorof transcription 5

SV40:

simian virus 40

TEL:

ets variant gene 6

TDLU:

terminal duct lobular unit

TGFα:

transforming growth factor alpha

Tyk2:

tyrosine kinase 2

WAP:

whey acidic protein

Wnt1:

wingless-related MMTV integration site 1

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Acknowledgments

This work was supported, in part, by the Public Health Service grant DK52013 (to H.R) as well as grants CA101841 (to H.R and K.U.W.), and CA117930 (to K.U.W.) from the National Cancer Institute.

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Authors and Affiliations

  1. Eppley Institute for Research in Cancer and Allied Diseases and the Department of Pathology and Microbiology, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, NE, 68198, USA

    Kay-Uwe Wagner

  2. Kimmel Cancer Center, Department of Cancer Biology, Thomas Jefferson University, Philadelphia, 233 S. 10th St, BLSB 330, PA, 19107, USA

    Hallgeir Rui

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  1. Kay-Uwe Wagner
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  2. Hallgeir Rui
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Correspondence to Kay-Uwe Wagner or Hallgeir Rui.

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Wagner, KU., Rui, H. Jak2/Stat5 Signaling in Mammogenesis, Breast Cancer Initiation and Progression. J Mammary Gland Biol Neoplasia 13, 93–103 (2008). https://doi.org/10.1007/s10911-008-9062-z

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  • DOI: https://doi.org/10.1007/s10911-008-9062-z

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