The Role of Her-2 in the Carcinogenesis of Breast Cancer – When and Where?

Her2 characterizes a distinct breast cancer progression pathway

In breast carcinomas overexpression and amplification of ErbB2/Her2/neu gene has been shown to be of prognostic value, leading to the identification of the oncoprotein as a target for therapeutic strategies, such as the inhibition by trastuzumab (Herceptin). However, the molecular mechanisms underlying Her2 action in breast cancer and its role in the development of breast carcinoma is still incompletely understood.

As in colon cancer a linear model of BC development was favored (Burstein et al. NEJM 350:1430–41, 2004) with hyperplasia, ductal carcinoma in situ (DCIS) and invasive carcinoma as a multistep-process. More recent data based on genetic and gene expression analysis gave evidence that distinct molecular events occur in normal breast epithelium giving rise to mainly two different molecular pathways. The first pathway is characterized by alterations including gain of 1q and loss of 16q underlying low grade DCIS and invasive ductal carcinoma (IDC). E-cadherin mutations charactize a low grade lobular pattern (lobular carcinoma in situ, invasive lobular carcinoma). The second pathway shows a multitude of genetic alterations, for example gains of 20q and 17q as well as losses of 13q and 17p as a sign of higher genetic instability (Bürger and Böcker, In: Böcker W Preneoplasia of the Breast, Saunders 2006, pp546).

Expression profiling data support this two tired system with low grade tumors expressing a unique set of genes that is rarely seen in high grade tumors (Moulis and Sgroi Breast Cancer Res 2008 epub). Sotiriou et al. (J Nat Cancer Inst 98:262–72, 2006) identified gene expression profiles that could classify the intermediate-grade tumors either into low-grade-like or high-grade like signatures. From these data it is highly unlikely that low and high grade tumors reflect just a continuum of tumor progression, they form rather distinct entities (Abdel-Fatah et al. Am J Surg Pathol 32:513–23, 2008). Based on this updated concept of BC carcinogenesis it become evident that amplification at 17q12 associated with overexpression of the ErbB2/Her2 tyrosine kinase receptor is characteristic of the high grade pathway with DCIS-HG showing Her2 positivity in about 60% and poorly differentiated IDC in about 20–25% of cases.

With respect to the molecular mechanisms of mammary carcinogenesis and progression, two questions are of central importance:

• What drives a normal breast cell to become an overexpressing atypical DCIS cell?

• Which role plays Her2 in DCIS to become an invasive and finally metastastic cancer?

Her2 in normal breast and its potential role in cell transformation

ErbB receptors transduce growth stimulatory signals into the cell and trigger proliferation in the morphogenesis of the mammary gland which mainly takes place after birth with ductal tree formation at puberty and generation of milk-producing lobuloalveolar structures during pregnancy. The two main receptor types involved in mammary gland morphogenesis are EGFR/Her1 and ErbB2/Her2. Both are members of the membrane-spanning type I receptor tyrosine kinase of which at present four subtypes (Her1–4) are known. Her2 is an orphan receptor unable to bind growth factors on its own. It forms heterodimers with ligand-activated Her1, Her3 and Her4. The number of receptors and their different complexes (4 receptors and 10 complexes) determine the tyrosine phosphorylation status and thus activation of different downstream cell signaling pathways controlling proliferation, apoptosis, differentiation and angiogenesis (Harari and Yarden Oncogene 19:6102–14, 2000).

Normal epithelial breast cells undergo cyclic proliferative and apoptotic changes as a result of hormonal influences. This guarantees a finally balanced cell renewal, a mechanism for elimination of genetically altered cells. Using in vitro and mouse models it could be shown that Her2 overexpression in normal mammary epithelial cells increases the proportion of stem/progenitor cells (Korkava et al. Oncogene June 30, 2008 epub). These cells escaped from apoptosis are most likely to form the pool of cells that are prone to acquire genetic damage (field defects) probably due to effects of endogeneous and exogeneous carcinogens.

Her2 and progression to invasive carcinoma

Overexpression of Her2 leads to a dominant ErbB2 homodimer formation in about 15% of IDC and 40–60% of DCIS with autophosphorylation being one of the mechanisms of autonomous signaling.

Today the transition of DCIS to IDC is mainly attributed to the formation of heterodimers between Her2 and other Her family members. E.g., ERGFR/Her2 heterodimerization is thought to act via actin reorganization and loss of adhesion mediating the invasive phenotype (Brand, In: Böcker W Preneoplasia of the Breast, Saunders 2006, pp556).

Using gene expression profiling and transgeneic mouse model systems BC can be devided into different molecular subtypes defining different prognostic groups (Fan et al. NEJM 355:560–9, 2006). Tumors derived from Her2 overexpression form one of the most distinct subgroups and show activation mainly within the G related signaling (GAP) pathway (->PI3K/Akt/mTOR). Thereby it turned out that Her2/Her3 heterodimers are of importance to maintain cell proliferation, whereas EGFR is dispensible (Lee-Hoeflich et al. Cancer Res 68:5878–87, 2008). Her3 binds a number of ligands with high affinity, but harbors an impaired tyrosine kinase. In Her2-amplified breast cancer tissues Her3 is preferentially trans-activated/-phosphorylated. This leads to activation of PI3K/Akt pathway, critically important in tumorigenesis in EGFR –/Her2 + tumors (Sergina et al. Nature 445:437–41, 2007). Both, Her3 transactivation as well as molecular changes including mutations of the downstream signaling partners (e.g. PI3K mutation, PTEN) impact on resistancy to targeted therapy (Stemke-Hafe et al. Cancer Res 68:6084–91, 2008).

Most recently it could also be shown that Her2 plays an important role regulating the stem/progenitor population driving tumorigenesis, invasion and thus the metastastic potential of BC. The exact relationship between Her2 overexpression/amplification status and CD44+/CD24- stem cells in BC has, however, to be elucidated (Fillmore and Kuperwasser, Breast Cancer Res 2008, epub).