Targeting receptor tyrosine kinase signaling cascade - sensitizing breast cancer to therapy

The second in a series of lab notes from our awardees, discussing their own research. Yinghui Zhang, Ph.D. - Postdoctoral Assoc., University of Leiden - The Netherlands

About 2 out of 3 of breast cancers are estrogen receptor (ER) positive. They require estrogen to grow. That is, estrogen binds to ER and ER is activated to promote cancer growth.Anti-estrogen drugs block estrogen-ER binding and prevent cancer cells from growing. However, a large proportion of patients eventually develop resistance. This can be due to aberrant signaling of receptor tyrosine kinases (RTKs) in breast cancer cells.

RTKs are proteins crossing over cell membrane. They receive signaling from growth factors outside of the cell and send messages via their downstream signaling cascades inside of the cell to stimulate cell growth. Many breast cancers have high levels of RTKs, including epidermal growth factor receptor (EGFR) and insulin-like growth factor 1 receptor (IGF1R). If over expressed or activated aberrantly, RTKs may continuously deliver power through RTK signaling networks to boost cancer cell growth.

RTK signaling networks are complicated. To know the truth of RTK signaling in anti-estrogen resistance, firstly, we have established stable expression of EGFR and IGF1R in ER positive breast cancer cell lines, namely MCF7/EGFR and MCF7/IGF1R, which have increased level of EGFR and IGF1R, respectively. In these cell models, we have demonstrated that high EGFR or IGF1R signaling induces anti-estrogen resistance through two well-known downstream signaling cascades, mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT). In this resistance, RTK signaling goes parallel to ER signaling and drives breast cancer cells to grow, regardless of anti-estrogen drug effect.

Next, in these anti-estrogen resistant cell settings, we have performed a high-throughput screen targeting all signaling proteins in RTK signaling networks and defined a panel of players, which are less-known or unknown in anti-estrogen resistance.

Here there is a working model proposing how RTKs pass on their signaling in breast cancer anti-estrogen resistance. This includes (1) estrogen (E) binding to ER, leading to ER activation and growth , (2) anti-estrogen drug, for example, tamoxifen (TAM), blocking ER activation, (3) phosphorylation (p) of ER by PI3K/AKT and MAPK/ERK signaling chains, which enables ER activation and disables tamoxifen blocking, (4) PI3K/AKT and MAPK/ERK signaling cascades going around ER action and inducing growth, and (5) less-known and unknown signaling cascades downstream of RTKs, which may bypass ER action or modify ER action by phosphorylation to promote growth, thereby leading to resistance.

Currently, I am working with the following specific objectives.

1.What are the roles of those less-known or unknown signaling players in breast cancer anti-estrogen resistance? We want to find novel targets.

2.How do RTKs communicate with these players to drive anti-estrogen resistance in our cell models? We want to know their pathways where they are targetable.

3.Are these players relevant to anti-estrogen resistance in ER positive breast cancer patients? We want to know their clinical translation.

4.Can chemists design novel compounds to target them? We want to know if they are druggable.

The aim of my research is to understand how RTKs mediate anti-estrogen resistance in ER positive breast cancers and discover novel targets blocking RTK signaling and (re-)sensitizing breast cancers to anti-estrogen therapy.