HOXA5 is found in the cells lining the breast, where it normally acts as a tumor suppressor and transcription factor. It helps new cells mature towards performing their final functions. The loss of HOXA5 causes cells to get stuck in their incomplete differentiation phase, during which they start dividing too much. This can lead to cancer. HOXA5 expression is lost in approximately 60-70% of all breast cancers, often occurring during an early stage of the disease. The loss of HOXA5 alone, however, is not always enough to start the breast carcinogenesis. Biochemical studies show that estradiol regulates HOXA5 gene expression in cultured breast cancer cells in vitro. HOXA5 expression is also upregulated in vivo in the mammary tissues of ovariectomized female rats. Estrogen-induced HOXA5 expression is coordinated by estrogen receptors: knockdown of either ERα or ERβ downregulated estrogen-induced HOXA5 expression. Additionally, ER co-regulators like histone acetyl-transferase CBP/p300 and histone methylases MLL2 or MLL3 and histone H3 trimethylation levels are enriched at the HOXA5 promoter bound to ER-alpha.
What seems certain is that HOX genes may be involved in the acquisition of tamoxifen resistance. Tamoxifen is a drug commonly used to treat patients with estrogen receptor positive breast cancer. Despite tamoxifen’s exceptional efficacy, approximately one-third of patients develop resistance to it, thus presenting a therapeutic challenge. Last year, a team of researchers from the Department of Anatomy and Embryology at Yonsei University College of Medicine in Seoul demonstrated that HOXA5 expression was significantly overexpressed in tamoxifen-resistant MCF7 breast cancer (TAMR) cells, due to the reduced binding of methylated histones to chromatin protecting proteins (BETs). The upregulation of HOXA5 led to the activation of the cellular PI3K/AKT cascade, which in turn led to the reduction of p53 and p21 proteins, making TAMR cells less susceptible to growth arrest and genetically programmed death. Thus HOX genes may be involved in aspects of tumor biology related to drug resistance. But now, researchers at the Johns Hopkins Kimmel Cancer Center have revealed how one of the members of the HOX family, the HOXA5 gene, may function to suppress the formation of breast tumors.
Their new study indicates that it interacts with another protein in an inflammatory cellular pathway, enhancing that protein’s cancer-suppressing properties. The work is now published in the journal Cancer Research. In studies in breast cancer cell lines and in mice, the team found that HOXA5 has a partner: it binds to and stabilizes the cellular protein I-kappa B alpha (IκB-α), which in turn inhibits NF-kappa B (NF-κB), a notorious transcription factor involved in inflammation, immunity and cell proliferation. Typically, NF-κB drives transcription of many cancer-causing genes, then IκB-α disrupts it. When HOXA5 is present, it is able to help IκB-α suppress NF-κB activity more potently, but when HOXA5 is lost the effect of IκB-α on NF-κB is reduced and the potential for the development of cancer is greater. In laboratory studies, the team studied a non-malignant breast epithelium that contained mutations in key breast cancer genes. Breast cancer cells sometimes become resistant to endocrine treatment by acquiring mutations in the PIK3CA gene, or resistant to anti-HER2 therapy through mutations in the HER2 gene.
In cells harboring mutations in the HER2 and PIK3CA genes, loss of HOXA5 induced the initiation of precancerous activity. When injected into mouse mammary ducts, the cells produced invasive tumor growth. The NF-κB pathway was significantly upregulated in cells after HOXA5 was silenced. As a result of the activation of the NF-κB pathway, multiple NF-κB target genes involved in exacerbating cancerous changes, such as IL-6 and COX2, were also upregulated. 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. A new avenue of research undertaken by the research team is to investigate how lost HOXA5 can be replaced or restored, so that its tumor-suppressing functions can be restored in cells. But it takes time and funding, some of which was provided by the Avon Foundation for Women for this work.
Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Advised in this website
Pai P, Wang G et al. Cancer Res 2022; 82(20):3802.
Kim CY et al. Anticancer Res. 2021; 41(7):3409-17.
Kim CY et al. J Cancer. 2021; 12(15):4626-4637.
Hussain I et al. Front Genet. 2020 Dec; 11:592436.
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