Researchers at Johns Hopkins Kimmel Cancer Center have revealed how the HOXA5 gene can work to suppress the formation of breast cancers. A new study indicates that it binds to another protein in an inflammatory cellular pathway, thus boosting the anti-cancer properties of this protein.
A description of this work was published on October 15 in the journal cancer research.
HOXA5 is found in cells that line the breast, where it normally functions as a tumor suppressor and transcription factor. It helps new cells mature and perform their ultimate functions, says study lead author Saraswati Sukumar, MD, professor of oncology and pathology at Johns Hopkins University School of Medicine, who has been studying this protein for 25 years.
The loss of HOXA5 has the consequence of stopping the cells in their stage of incomplete differentiation, during which they begin to divide excessively. It can lead to cancer. HOXA5 expression is lost in approximately 60-70% of all breast cancers, often occurring early in the disease. However, loss of HOXA5 alone isn’t always enough to trigger the breast cancer process, and Sukumar’s team set out to understand the other steps involved.
By studying breast cancer cell lines and mice, Sukumar’s team discovered that HOXA5 has a partner: it binds to and stabilizes the cellular protein I kappa B alpha (IκB-α), which inhibits in turn the protein complex NF-kappa B (NF-κB). Typically, NF-κB rushes to the nucleus and starts transcription of many carcinogenic genes, then IκB-α stops it. When HOXA5 is present, it is able to help IκB-α suppress NF-κB activity more effectively, but when HOXA5 is lost, the effect of IκB-α on NF-κB is reduced, and the potential for cancer development is greater.
Our studies show that HOXA5 acts to suppress a very important inflammatory pathway, which has been shown to be a promoter of tumor development. Understanding precisely how this happens is of great importance, because increasing the amount of HOXA5 in these tumor cells might be a solution to try to reverse the process of tumor formation. »
Saraswati Sukumar, MD, Professor of Oncology and Pathology at Johns Hopkins University School of Medicine.
In the lab, lead author and postdoctoral fellow Priya Pai studied a cell line from non-malignant tissue lining the breast (epithelial cells) that contained mutations in key breast cancer genes. Breast cancer cells sometimes become resistant to endocrine therapy by acquiring mutations in the PIK3CA gene, or resistant to anti-HER2 therapy by mutations in the HER2 gene. In cells that had mutations in the HER2 and PIK3CA genes, loss of HOXA5 induced the onset of precancerous activity. Injected into mouse mammary ducts, the cells produced invasive tumor growth. The NF-κB pathway was significantly up-regulated in cells following injection. HOXA5 has been silenced. Following NF-κB pathway activation, several NF-κB target genes involved in exacerbating cancerous changes, such as IL-6 and COX2, were also up-regulated. Collectively, the data suggest that the presence of HOXA5 suppresses malignancy in breast epithelial cells by attenuating the action of NF-κB through stabilization of its inhibitor, IκB-α.
According to Sukumar, a new avenue of research is to investigate how to replace or restore lost HOXA5 in order to restore its tumor suppressing functions in cells.
This work was supported by the Avon Foundation for Women.
The other researchers were Guannan Wang, Wei Wen Teo, Diana Raez-Rodriguez, Kathleen Gabrielson, Bradley Downs and Akanksha Aggarwal from Johns Hopkins, and Balázs Győrffy from Semmelweis University in Budapest, Hungary.
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Journal reference:
Pai, P., et al. (2022) HOXA5-mediated stabilization of IκBα inhibits the NF-κB pathway and suppresses malignant transformation of breast epithelial cells. Cancer research. doi.org/10.1158/0008-5472.CAN-21-4277.
