Vincent L. Cryns, MD

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 have identified the mechanisms by which p53 and Akt are regulated by these proteins and how the p53 and Akt cancer pathways are linked. The team also discovered that αβ-crystallin and Hsp27 each directly bind and regulate other key cancer drivers to promote tumor growth. Over the past year, the team studied how these cell stress proteins regulate other key cancer drivers, including NRF2, a protein that drives aggressive tumor growth and drug resistance. Their results suggest that these cell stress proteins promote tumor growth by acting on many cancer-promoting targets. They found that blocking αβ-crystallin and/or HSP27 by genetic strategies triggers tumor cells to die. These findings may lead to fundamentally new treatment approaches for TNBC that inhibit multiple cancer drivers such as mutant p53, Akt and NRF2 simultaneously (instead of blocking them individually) by targeting these cells stress proteins.

What’s next

In the coming year, Drs. Cryns and Gradishar will continue to investigate their hypothesis that cell stress proteins associate with key cancer drivers, such as mutant p53 and NRF2, to recruit small heat shock proteins like Hsp27, which in turn stabilize the cancer drivers and regulate their activity. The team will use model systems to test their hypothesis that blocking αβ-crystallin and/or Hsp27 by genetic strategies will eliminate mutant p53 and NRF2, trigger cell death and inhibit tumor growth, and metastases.