Despite the overall success of hormone therapy, breast cancer tumors in patients with metastatic disease often fail to respond. One new mechanism that can explain resistance to hormone therapy in breast cancer involves two significant changes in the cells––overexpression of the FOXA1 gene and increased production of interleukin (IL)-8.
Researchers at Harvard Medical School, Baylor College of Medicine, Oregon Health and Science University, Washington University, and the University of Houston propose that designing drugs directed at IL-8 or other FOXA1-dependent proteins could potentially result in therapies for hormone-resistant breast cancer tumors as well as improved diagnostic tools. Their findings were published in the Proceedings of the National Academy of Sciences.
Approximately 75% of breast cancers have estrogen receptors; hence, they are called estrogen receptor (ER)-positive cancers. Original ER-positive breast cancer cells depend on estrogen to grow, and therapies that make the estrogen unavailable to cells (i.e., hormone therapies) can result in long-term remission in some patients. Tamoxifen, one of several types of hormone therapy, works by binding to and blocking the estrogen receptor on cancer cells. However, most patients with metastatic disease whose tumors initially respond to hormone therapy eventually relapse and die because of acquired resistance to hormone treatment.
To study how cells become resistant to hormone therapy, the scientists took a number of laboratory breast-cancer cell lines that were susceptible to hormone treatment, called parental cells, and from each they developed cells lines that were resistant to tamoxifen. When the scientists knocked out the FOXA1 gene in tamoxifen-resistant cells, the cells became susceptible to tamoxifen therapy, confirming that the FOXA1 gene plays an important role in tamoxifen resistance.
The function of the FOXA1 gene is to promote the expression of many other genes. In this case, “we found that overexpression of FOXA1 results in the activation of a series of genes that increase the metastatic potential of cells––for instance, genes that favor cell migration and development of blood vessels,” said co-senior author Dr. Rachel Schiff.
At the top of the list of genes activated by overexpression of FOXA1 was the gene for IL8, which also contributes to cell survival.
To determine the relevance of these results in actual ER-positive breast tumors, the scientists analyzed samples from a tumor bank and found tumors with high levels of both the FOAX1 gene and IL8 protein.
“We see a tremendous therapeutic potential in this study,” said first author Dr. Xiao-yong Fu. “We can potentially design drugs directed not only to IL8 but also several of the genes activated by FOXA1 in tamoxifen-resistant cells to try to control the development of their metastatic potential.”
Source: Baylor College of Medicine; October 3, 2016.