P95 HER2 fragments and breast cancer outcome

Abstract

HER2 is a 185-kDa transmembrane oncoprotein encoded by the HER2 gene. It is located on chromosome 17q21 and is overexpressed in approximately 15% of invasive breast cancers. In addition, it is a poor prognostic factor for survival and disease progression. Approximately 30% of HER2-positive tumors also express a series of carboxy-terminal HER2 fragments known as p95HER2, in addition to the full-length HER receptor. Previous studies have found that p95HER2 represents an independent prognostic marker in patients with HER2-positive disease. Moreover, p95HER2 status might be a decisive factor when choosing between different therapies because p95HER2 fragment-positive tumors are resistant to trastuzumab but respond to tyrosine kinase inhibitors, such as lapatinib, as do p95HER2-negative tumors. p95HER2 fragments arise through at least two different mechanisms: proteolytic shedding of the full-length p185HER2 receptor extracellular domain and translation of HER2 mRNA from internal initiation codons. The present review is based primarily on recent studies suggesting p95HER2 constitutes a new surrogate marker for an aggressive HER2-positive breast cancer subtype with distinct clinical and biological features.

Keywords::

• breast cancer outcome
• p185HER2
• p95HER2 fragment
• proteolytic shedding and translation of HER2

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• The following mechanisms have been identified as trastuzumab resistance mechanisms in clinical and preclinical studies: expression of p95HER2 (a form of truncated HER2 that does not have an outer-cell attachment domain), HER2 transactivation by different tyrosine kinases such as IGF-1R, or loss of phosphatase-tensin homolog expression and increased PI3K/Akt signaling due to PI3K mutation.

• p95HER2 fragments have been demonstrated to have a role in the resistance to anti-HER2–targeted therapies.

• p95HER2 fragments arise through at least two different mechanisms: proteolytic shedding of the extracellular domain of the full-length p185HER2 receptor and translation of HER2 mRNA from internal initiation codons.

• HER2 cleavage has been attributed to various zinc-containing metalloproteinases, including the members of a disintegrin and metalloproteinase and matrix metalloproteinase families. A fragment that is generated as a result of this shedding is termed 648-carboxy terminal fragment (CTF) p95HER2 (95–100 kDa).

• Alternative initiation of HER2 mRNA from methionine codons 611 and 687 leads to synthesis of two CTFs that are 100–115 kDa and 90–95 kDa, known as 611-CTF and 687-CTF, respectively.

• The membrane-truncated p95HER2 fragments are active, but have different potencies. The activity of 648-CTF truncated p95HER2 fragments was comparable to that of full-length receptor (p185HER2). However, expression of the 611-CTF p95 fragments resulted in more rapid and acute activation of different signaling cascades.

• One-third of HER2-positive tumors express p95HER2, which distinguishes a subgroup with worse outcome, and may be useful in predicting responses to HER2-targeted therapy.

• Poor response to trastuzumab in patients who express p95HER2 has paved the way for alternative strategies to inhibit the HER2 oncogenic pathway. Lapatinib is a small molecule tyrosine kinase inhibitor with dual action; the drug inhibits both ERBB1 and ERBB2.

Notes