HOX genes regulate cell differentiation during embryonic development. Here we demonstrate HOXA10 expression in both benign and malignant adult human breast tissue and in MCF-7, but not BT20 breast cancer cells. We have previously shown that HOXA10 mediates uterine differentiation in response to estrogens. The mechanism of action of estradiol and other estrogen receptor modulators on breast cancer cell growth is still poorly understood. MCF-7 cells, which are ER (+) and express HOXA10, were used to assay the effect of estradiol and tamoxifen on HOXA10 expression. Semi-quantitative RT-PCR and northern analysis revealed that treatment with either estradiol or tamoxifen increased HOXA10 mRNA expression. BT20 cells, which are ER (-) and do not endogenously express HOXA10, were used to assay the effect of increased HOXA10 expression on p53 expression and on the invasive phenotype. Constitutively expressing HOXA10 in BT20 cells increased p53 protein expression. Increased HOXA10 also reduced invasiveness through matrigel. The mechanism by which estrogen and other estrogen receptor modulators influence both normal breast development as well as breast cancer may involve the regulation of developmental control genes such as HOXA10; HOXA10 in turn regulates expression of key downstream genes such as p53 and regulates tumor cell functional phenotype.