Review
The role of HER2 in early breast cancer metastasis and the origins of resistance to HER2-targeted therapies

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Abstract

The HER2 gene encodes the receptor tyrosine kinase HER2 and is often over-expressed or amplified in breast cancer. Up-regulation of HER2 contributes to tumor progression. Many aspects of tumor growth are favorably affected through activation of HER2 signaling. Indeed, HER2 plays a role in increasing proliferation and survival of the primary tumor and distant lesions which upon completion of full transformation cause metastases. P185HER2/neu receptors and signaling from them and associated molecules increase motility of both intravasating and extravasating cells, decrease apoptosis, enhance signaling interactions with the microenvironment, regulate adhesion, as well as a multitude of other functions.

Recent experimental and clinical evidence supports the view that the spread of incompletely transformed cells occurs at a very early stage in tumor progression. This review concerns the identification and characterization of HER2, the evolution of the metastasis model, and the more recent cancer stem cell model. In particular, we review the evidence for an emerging mechanism of HER2+ breast cancer progression, whereby the untransformed HER2-expressing cell shows characteristics of stem/progenitor cell, metastasizes, and then completes its final transformation at the secondary site.

Section snippets

HER2 identification and characterization

Our initial studies of oncogenes were an extension of our search for a relationship between transforming genes and tumor antigens (Greene et al., 1982). In the early 1980s, we (Schechter et al., 1984) isolated an oncogene from B104 tumors derived from neuroblastoma neoplasms that occurred in the offspring of rats treated during gestation with the carcinogen ethylnitrosourea. We identified the neu oncogene, named after its tissue of origin, as responsible for the malignant phenotype of the

HER2 expression patterns in early lesions

Notably, up-regulation of HER2 levels can be readily detected in human breast tissues that show the early signs of transformation but have not yet been completely transformed. Completely transformed cells are able to grow in an anchorage-independent fashion in vitro and also grow in vivo. Incompletely transformed cells display one, but not both, of these traits. Table 1 summarizes HER2 expression within breast lesions at various stages of cancer progression. Generally, HER2 is absent or

Dimeric forms of erbB receptors

In addition to their expression, we also examined how the p185c-neu proto-oncogenic receptors become activated at a biochemical level. David Stern at Yale (Stern et al., 1988) and our laboratory (Kokai et al., 1988) found that p185c-neu was phosphorylated in cells expressing both EGFR and p185c-neu proteins. We discovered that transfecting cells with both proto-oncogenic c-neu and EGFR enabled the malignant transformation of the cells, while transfecting either of them alone did not.

HER2 promotes early dissemination of incompletely transformed cells

Metastasis, the primary cause of morbidity and mortality of most cancers, is an extremely complex and highly organized process that is organ-specific and involves numerous reciprocal interactions between the cancer cells and the host (Fidler and Hart, 1982, Steeg, 2003, Yeatman and Nicolson, 1993). The stage at which individual cells leave the primary tumor was unclear, and new data have caused us to rethink this process. The previous metastasis model suggested that epithelial cells

HER2 promotes metastases

Not only is HER2 expressed in metastases, it also promotes that phenotype. It has been shown that when paired primary tumor and distant metastatic lesions are compared, approximately 94% and 93% of samples have a concordant HER2 status when analyzed by IHC or FISH, respectively (Gancberg et al., 2002). Therefore, routine determination of HER2 on metastatic sites is not needed when FISH results from the primary tumor have been obtained. One of the many functions of HER2 in metastatic cells may

HER2 regulates mammary stem/progenitor cell populations

All tissues in the body are derived from organ-specific stem cells that have the capacity to undergo self-renewal, differentiate into the cell types that comprise each organ, and help maintain tissue integrity. There is evidence that certain tumors are derived from stem cells or from early descendents of stem cells. Bonnet and Dick discovered that leukemia is driven by a small population of leukemia cells that have the ability to perpetually self-renew. They termed this population cancer stem

HER2-targeted therapies

Studies from our laboratory contributed to the development of HER2-targeted therapies. We (Drebin, 1985, Drebin, 1986) discovered that down-regulation of cell surface p185neu blocks downstream signaling and reverses the malignant phenotype of neu transformed cells. We purified p185neu reactive monoclonal antibodies (IgG2a) capable of cross-linking the receptor molecules of the neu-transfected NIH3T3 cells. This led to rapid p185neu down-regulation and an increased rate of its degradation. The

Targeted therapies prevent pre-malignant lesions from progressing

Since HER2 plays such an important role in early metastasis, targeted therapies may be critical to prevent pre-malignant lesions from developing into IBC. We have shown that HER2-targeted antibodies not only inhibit growth of already established tumors, but also can prevent tumor development in transgenic mice over-expressing the activated neu oncogene in mammary epithelial cells (Katsumata et al., 1995). In this study, treatment of transgenic animals after 20 weeks of age but before tumor

Resistance to HER2-targeted therapeutics

A large percentage of HER2-positive cancers demonstrate predisposition to resistance to HER2-targeted therapeutics (Zhang et al., 2007). In addition, many tumors that are initially responsive to HER2-targeted therapies become refractory following treatment (Zhang et al., 2007). An increasing body of evidence indicates that the resistant phenotype can arise from diverse adaptive and genetic changes within transformed cells, which allow the cells to survive in the presence of the HER2-targeting

Heteromer formation and resistance

The HER2/EGFR heterodimer may undergo antibody-induced internalization, ubitiquination, and proteolysis (Gilboa, 1995, Maier, 1991, Qian, 1997, Srinivas, 1993). The internalization of HER2/EGFR represents a mechanism by which the HER2-specific antibodies disable the transforming activity of the receptor. HER2 internalization and degradation involve clathrin-mediated endocytosis and trafficking of the cell surface proteins from the endosomal compartment to the lysosome (Maier et al., 1991).

Conclusion

Metastasis can occur very early during breast cancer progression and exist in different locations with an incompletely transformed phenotype. Despite complete removal of their primary tumor, patients with localized, lymph node-negative tumors also relapse, demonstrating that disseminated tumor cells must have spread before surgery or even diagnosis.

Recent studies have found breast tumor cells have cancer stem cell properties and are regulated by HER2. HER2 is responsible for an increase in

Acknowledgments

This work was supported by the National Institutes of Health Grant CA055306 (to M.I.G). J.A.F. was supported by National Institutes of Health NRSA Training Grant T32CA09140.

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