William J. Gradishar, MD, FACP

Improving outcomes in breast cancer by identifying aberrant cell processes that lead to tumor formation and progression.

Impact

Basal-like triple-negative breast cancers are aggressive and lack targeted therapies because they do not depend on the estrogen or progesterone hormones or HER2 for growth, hence the term “triple-negative.” Drs. Cryns and Gradishar are studying cell stress proteins called αβ-crystallin and Hsp27, which interact with cancer-promoting proteins and contribute to the aggressive behavior of basal-like/triple-negative breast cancer (TNBC) by. They have shown that αβ-crystallin and Hsp27 interact with a mutant form of p53, the most commonly mutated gene in cancer, and link p53 to Akt, a growth-promoting protein that is often upregulated in cancer. Their work may lead to the identification of new approaches to target oncogenes in a broad spectrum of breast tumors.

Progress Thus Far

The team has discovered that mutant p53 depends on αβ-crystallin and Hsp27 to promote tumor formation. They found that αβ-crystallin and Hsp27 each directly bind and regulate other key cancer drivers to promote tumor growth. The team also identified the mechanisms by which p53 and Akt, two common cancer drivers, are regulated by these proteins. Drs. Cryns and Gradishar also determined that blocking αβ-crystallin and Hsp27 triggers tumor cells to die. Additionally, their work revealed a previously unrecognized link between p53 and Akt, two common cancer drivers that were thought to be unrelated. The team discovered that this pathway is activated by a complex involving these stress proteins and others. These findings could lead to fundamentally new treatment approaches for TNBC.

What’s next

In the coming year, Drs. Cryns and Gradishar will use genetic approaches to block αβ-crystallin and Hsp27 and examine how this affects tumor growth and chemotherapy resistance. Their goal is to ultimately develop therapies to disrupt multiple cancer drivers simultaneously.