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HER2 dimerization: a key component of oncogenic signaling in HER2+ breast cancer

The HER family

The HER family is composed of 4 receptor tyrosine kinases that must pair, or dimerize, to activate downstream signaling¹:

• EGFR (HER1)
• HER2
• HER3
• HER4

The role of dimerization in HER2+ disease

Preclinical studies indicate that HER dimerization, or receptor pairing, is a critical step in HER activation.¹ While the receptors of the HER family are important mediators of normal cell growth and development, HER activation has also been implicated in cancer development and progression.¹⁰

In normal cell growth, dimerization is an essential requirement of HER functionality and signaling, and it occurs between 2 of the same receptors (homodimerization) or 2 different receptors (heterodimerization).¹

However, in HER2+ disease, HER2 overexpression is associated with excessive dimerization that contributes to cell survival, cell proliferation, and tumorigenesis.⁶

The HER family of receptors.

Ligand binding and HER activation

Each HER family receptor has 3 domains: the extracellular, transmembrane, and intracellular domains, all of which are necessary for receptor activation and intracellular signaling. In order to activate downstream signaling, receptors must dimerize utilizing the dimerization sub-domain (known as sub-domain II) located on the extracellular domain of the receptor.¹⁰

EGFR (HER1), HER3, and HER4 naturally exist in a “closed” conformation. In the closed position, the dimerization sub-domain (sub-domain II) is hidden or inaccessible, and as a result, the receptor is unable to form dimers. Ligand binding to these receptors leads to a conformational change, exposing sub-domain II and enabling the receptor to dimerize and initiate downstream signaling. HER2 is the only receptor in the HER family that exists in a continuously open conformation ready to dimerize without the need for ligand binding.^3,11

HER2 dimerization: critical for tumor growth

When HER family members dimerize, the intracellular domains of the paired receptors are phosphorylated, resulting in the activation of cell proliferation and cell survival pathways.¹²

In HER2+ disease, the overexpression of HER2 is associated with overactive HER2 dimerization, abnormal signaling, and ultimately tumor growth.⁶