Abstract
Abstract Members of the Retinoic acid receptor (RAR) and HOX gene families are known to be associated with cellular differentiation. Nonetheless, how HOX genes drive differentiation in mammalian cells is poorly understood. HOX genes are transcription factors that orchestrate body segmentation during embryogenesis. But the continued expression of several members in adulthood indicates the necessity of their biological functions in specifying cell fate in adulthood. The mammary gland is an organ that continues to go through multiple cycles of development during life. Here, loss of specific HOX genes could be detrimental to normal development. We have previously shown that expression of HOXA5, a downstream target of the retinoic acid signaling pathway, is often lost in breast cancer. Loss of HOXA5 expression correlates with increasing pathological grades of breast cancer. Expression array analysis of HOXA5-depleted MCF10A (immortalized line of human breast epithelium) revealed its potential role in regulating several traits of the epithelial lineage, including expression of E-cadherin and CD24. Depleting HOXA5 in MCF10A enhanced cell motility, invasiveness and increased stem-cell population (CD24lo/CD44hi). Using an inducible HOXA5-depletion system, differentiation of the stem cells in MCF10A was shown to be mediated by HOXA5. Conversely, ectopic expression of HOXA5 in SUM149 breast cancer cells significantly reduced plasticity and stem cell population, confirmed by in vivo limiting dilution assays in mice. MCF10A-KRAS-HOXA5 depleted cells formed invasive structures in 3D matrigel cultures, and formed larger tumors, implanted orthotopically in mice. MCF10A-KRAS-tumors were histologically dedifferentiated and lost expression of luminal cell markers such as E-cadherin and cytokeratin 18. Collectively, our findings demonstrate the role of HOXA5 in retinoid-induced cell differentiation by regulating cell fate specific surface adhesion molecules. Citation Format: Wei Wen Teo, Vanessa Merino, Sean Cho, Preethi Korangath, Neil M. Neumann, Andrew J. Ewald, Saraswati Sukumar. HOXA5 inhibits cell plasticity and stemness in breast cancer cells by reinforcing epithelial traits. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1526. doi:10.1158/1538-7445.AM2015-1526
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