Eric Chang Lab


About the Lab


We are interested in signal transduction cross-talk between RAS and the estrogen receptor in the control of breast tumor growth, treatment resistance, and metastasis. The ultimate goal is to discover clinically relevant personalized treatment strategies.

Research Interests

Hijacking the cell’s growth signals is a key mechanism driving tumorigenesis, drug resistance, and metastasis. Estrogen receptor (ER) is a transcription factor that activates gene expression in the presence of estrogen, which is a growth signal for breast cells. ER+ breast cancer is the most common form of breast cancer, occurring in over 150,000 women annually in the US alone. While many anti-ER agents (e.g., tamoxifen) are available, resistance to treatment can occur, which is often driven by RAS activation. RAS proteins are important growth signal transducers, and mutations affecting RAS genes are found in over 30% of tumors. One of our major projects is to better define how ER and RAS are connected, such that we can learn to untangle and block their actions leading to better treatments.

NF1 as a dual repressor for both RAS and ER

NF1 is a key tumor suppressor gene. It was first discovered to be inactivated at the germline level to induce neurofibromatosis type 1, which is the common genetic disorder. NF1 has been known for decades as a repressor of RAS. However, guided by a large clinical study to seek mutations that can drive tamoxifen resistance, we discovered that NF1 can also directly interact with ER to function as a transcriptional corepressor, independent of RAS. Thus, NF1 loss can bypass ER blockade by not only activating RAS but also ER itself. We defined a combination therapy that can block both ER and RAS. When given to a xenograft mouse model derived from a patient who failed several lines of anti-ER therapies, the ER/RAS combination therapy led to efficient tumor regression. We are launching a Phase-II clinical trial (NCT05554354) with support from the NCI ComboMATCH program to test this strategy in patients.

NRAS as a driver to promote basal-like (ER–) tumors.

While the majority of breast cancers are ER+, up to 20% of breast tumors belong to the basal-like subtype that is usually ER– and much more aggressive. The origin of these ER– tumors is unclear. However, because early stage premalignant breast tumors are mostly ER+, it seems logical that ER– tumors are evolved from ER+ tumors. We found that one of the RAS genes, NRAS, when activated in premalignant ER+ tumors, can drive the formation of basal-like ER– tumors. Targeting this NRAS pathway may stop cancer progression into a more aggressive stage early in its track