HOXA9 regulates BRCA1 expression to modulate human breast tumor phenotype

Abstract

Breast cancer 1, early onset (BRCA1) expression is often reduced in sporadic breast tumors, even in the absence of BRCA1 genetic modifications, but the molecular basis for this is unknown. In this study, we identified homeobox A9 (HOXA9) as a gene frequently downregulated in human breast cancers and tumor cell lines and noted that reduced HOXA9 transcript levels associated with tumor aggression, metastasis, and patient mortality. Experiments revealed that loss of HOXA9 promoted mammary epithelial cell growth and survival and perturbed tissue morphogenesis. Restoring HOXA9 expression repressed growth and survival and inhibited the malignant phenotype of breast cancer cells in culture and in a xenograft mouse model. Molecular studies showed that HOXA9 restricted breast tumor behavior by directly modulating the expression of BRCA1. Indeed, ectopic expression of wild-type BRCA1 phenocopied the tumor suppressor function of HOXA9, and reducing BRCA1 levels or function inhibited the antitumor activity of HOXA9. Consistently, HOXA9 expression correlated with BRCA1 in clinical specimens and with tumor aggression in patients lacking estrogen receptor/progesterone receptor expression in their breast tissue. These findings indicate that HOXA9 restricts breast tumor aggression by modulating expression of the tumor suppressor gene BRCA1, which we believe provides an explanation for the loss of BRCA1 expression in sporadic breast tumors in the absence of BRCA1 genetic modifications.

HOXA9 is Underexpressed in Cervical Cancer Cells and its Restoration Decreases Proliferation, Migration and Expression of Epithelial-to-Mesenchymal Transition Genes

“…The HOXA cluster has been related with normal development of urogenital tracts (Burel et al, 2006); in particular, HOXA9 and -11 are important in controlling the embryonic development of Müller ducts (Hsieh-Li et al, 1995). With regard to HOXA9, this gene has been found overexpressed in hematological malignancies (Milne et al, 2010){Zhao, 2014 #203}, but in solid tumors, especially epithelial tumors, it has been observed as downregulated (Gilbert et al, 2010;Chen et al, 2012;Hwang et al, 2015). These observations were in agreement with our observations.…”

“…The tumor suppressor function of HOXA9 has been extensively investigated in breast cancer, where it has been shown that HOXA9 directly regulates BRCA1 and other genes involved in invasion, growth, and metastasis (Gilbert et al, 2010). Uchida et al observed that high methylation levels of HOXA9 are associated with a high risk of metastatic tumors; in addition, the authors found that reduced HOXA9 expression confers an advantage on cell growth (Uchida et al, 2014); these observations are consistent with our results in CC-derived cells.…”

The role of components of the chromatin modification machinery in carcinogenesis of clear cell carcinoma of the ovary (Review)

“…HOXA9 expression is spatially and temporally regulated during hematopoiesis and embryonic development. Reduced HOXA9 transcript levels are reportedly associated with breast cancer aggression, metastasis and patient mortality (31). ARID1A also directly interacts with HIC1 (hypermethylated in cancer 1), a tumor suppressor gene, which is epigenetically inactivated in numerous human cancers (32,33).…”

Genetic Factors Influencing the Risk and Clinical Outcome of Neuroblastoma

“…The HOXA9 (homeobox A9) gene encodes a sequence-specific transcription factor which is part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis of an organism (The NCBI handbook, 2002). Dysregulated expression of HOXA9 has been described in several malignancies including non-small-cell lung cancer (Calvo et al, 2000) and breast cancer (Gilbert et al, 2010). Neuroblastoma cell lines treated with demethylating agents have been reported to display increased levels of HOXA9 gene expression (Margetts et al, 2008).…”