Why do breast cancer tumors that are initially responsive to hormonal therapy develop resistance down the road?

 

That is the central clinical question for Dr. Adam Lerner. Several years ago, as an oncologist and researcher at Boston University School of Medicine, he discovered that a protein made by a gene he had successfully cloned binds to another protein in a very specific way. Remarkably, both gene products were subsequently implicated in the mechanism by which breast cancer cells develop resistance to hormonal therapies. Dr. Lerner is now examining the mechanism by which these proteins induce resistance to commonly used hormonal treatments for breast cancer.

 

Increased expression of either of the pair of proteins, known as BCAR3 and BCAR1, allows estrogen-receptor positive (ER+) breast cancer cells to grow, even in the absence of estrogen, and even when they are treated with Tamoxifen or Faslodex. "The majority of ER+ patients do well with Tamoxifen and other hormonal therapies, but they are susceptible to developing resistance to the drugs over time. We want to figure out why, so we can develop therapies to overcome that resistance," says Dr. Lerner.

 

Dr. Lerner's study aims to understand the signaling pathways and interaction of the two proteins in the hope of figuring out how to interfere with these processes at the molecular level. He and his three lab partners are now testing mutants of the BCAR3 and BCAR1 proteins in breast cancer cell lines in an effort to account for resistance to Faslodex, a common treatment for ER+ breast cancer. "We are exploring what sort of mutations eliminate the ability to produce resistance. If we can get at the exact mechanism, we hope to develop drugs that might block the original function of the protein," he explains.

 

"What we're seeing is that over-expression of these proteins appears to alter breast cancer cells such that they can now receive survival and proliferation signals from their surrounding environment, rather than from estrogen signaling," notes Dr. Lerner. His lab has also noticed that when BCAR3 is overexpressed, the cells change from an epithelial appearance to more of a fibroblast appearance, that is, they become more individualized and lose the tendency to grow in cohesive sheets. In addition, they become more motile and invasive and there is a shift in how they behave toward one another. Of note, breast cancers that develop resistance to hormonal therapies are also known to frequently simultaneously acquire greater metastatic and invasive behavior.

 

The ideal outcome of his study, says Dr. Lerner, would be the identification of the precise signaling pathway for the interaction of BCAR3 and BCAR1 and the development of a means to interrupt that activity using small molecule inhibitors. Eventually, that could lead to the establishment of a screening test for the proteins. "That could be an important breakthrough once we have the tools to combat the BCAR3/BCAR1 protein combination," he adds.