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Transforming growth factor alpha and mouse models of human breast cancer

Oncogene volume 19, pages 1085–1091 (2000)Cite this article

Abstract

Transforming growth factor alpha (TGFα) is a principal molecule in the normal and neoplastic development of the mammary gland. Binding of TGFα to the epidermal growth factor receptor (EGFR), activates the EGFRs' endogenous tyrosine kinase activity and stimulates growth of the epithelium in the virgin and pregnant mouse mammary gland. TGFα expression can be detected in breast cancer cells in vivo and in vitro and overexpression can elicit partial transformation or immortalized human and rodent mammary epithelial cells. Despite evidence implicating TGFα in the development of mammary neoplasia, the actual mechanism of TGFα-induced transformation is unclear. Transgenic mouse models targeting heterologus TGFα to the mammary gland have established TGFα overexpression can induce hyperproliferation, hyperplasia and occasional carcinoma. These transgenic studies demonstrated a facilitating, proliferative role for TGFα in the development of neoplasia and implicated several oncogenes that can cooperate with TGFα to transform the mammary epithelium. From studies of EGFR signaling pathways, inhibitory and modulating agents such as anti-EGFR antibodies and specific kinases inhibitors have been used to block the action of this pathway and prevent the development of TGFα-induced neoplasia and tumor formation. Studies in Stat5a knockout mice have established that the JAK2/Stat5a pathway can facilitate the survival of the mammary epithelium and can impact the progression of TGFα-mandated mammary tumorigenesis. Together these experiments indicate that TGFα and the EGFR signaling pathway are potentially amenable to therapies for treatment of human breast disease.

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Acknowledgements

This work is supported by a grant from the Breast Cancer Research Program from USMRMC DAMD 17-99-1-9328.

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  1. National Institutes of Health, National Institute of Digestive, Diabetes and Kidney Disease, Laboratory of Genetics and Physiology, Building 8, Room 111, Bethesda, 20892, Maryland, MD, USA

    Robin C Humphreys & Lothar Hennighausen

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Humphreys, R., Hennighausen, L. Transforming growth factor alpha and mouse models of human breast cancer. Oncogene 19, 1085–1091 (2000). https://doi.org/10.1038/sj.onc.1203278

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