Study Shows HOXA5 Impedes Breast Cancer Tumor Initiation and Progression

A team of cancer researchers has discovered that the HOXA5 (Homeobox protein Hox-A5) gene, which is not found in many breast cancers, acts as a tumor suppressor by regulating E-cadherin and CD24.

Loss of HOXA5 expression occurs frequently in breast cancer and correlates with higher pathological grade and poorer disease outcome. However, how HOX proteins drive differentiation in mammalian cells is poorly understood.

In order to better understand how HOXA5 works, investigators at Johns Hopkins University (Baltimore, MD, USA) evaluated the cellular and molecular consequences of the loss of HOXA5 in breast cancer development and growth.

They reported in the May 9, 2016, online edition of the journal Oncogene that analysis of global gene expression data from HOXA5-depleted MCF10A breast epithelial cells pointed to a role for HOXA5 in maintaining several molecular traits typical of the epithelial lineage such as cell-cell adhesion, tight junctions, and markers of differentiation. Depleting HOXA5 in immortalized MCF10A or transformed MCF10A-Kras breast cancer cells enhanced their self-renewal capacity and reduced expression of E-cadherin and CD24.

Cadherins (named for “calcium-dependent adhesion”) are a class of type-I transmembrane proteins. They play important roles in cell adhesion, ensuring that cells within tissues are bound together. Loss of E-cadherin function or expression has been implicated in cancer progression and metastasis. E-cadherin downregulation decreases the strength of cellular adhesion within a tissue, resulting in an increase in cellular motility. This in turn may allow cancer cells to cross the basement membrane and invade surrounding tissues.

The CD24 cell adhesion molecule is a glycoprotein expressed at the surface of most B-lymphocytes and differentiating neuroblasts. This gene encodes a sialoglycoprotein that is expressed on mature granulocytes and in many B-cells. The encoded protein is anchored via a glycosyl phosphatidylinositol (GPI) link to the cell surface.

Depletion of HOXA5 in mammary cells was found to lead to loss of epithelial traits, an increase in stem cell-like characteristics and cell plasticity, and the acquisition of more aggressive phenotypes.

“Learning more about the biological impact of the HOXA5 protein, which is absent so frequently in breast cancers, may eventually help scientists develop new therapies to treat this disease,” said senior author Dr. Saraswati Sukumar, professor of oncology and pathology at Johns Hopkins University. “HOXA5 regulates the production of two other proteins: CD24 and E-cadherin. Without CD24, the cells begin to revert toward a stem-like state, and without E-cadherin, cells lose some of the “glue” that binds them to other cells.”

Related Links:
Johns Hopkins University