The mammalian testis-determining gene Sry and the related Sox genes define a family of transcriptional regulators widely expressed during embryogenesis. Tightly controlled temporal profiles of expression are a feature of the Sox gene family and may be required for initiation of a cascade of gene expression, yet the molecular mechanisms that control Sox gene expression are unknown. We now show that human SOX4 is expressed in the normal breast and in
breast cancer cells. In these cells SOX4 is a
progesterone-regulated gene, the expression of which is increased by
progestins, leading to a marked increase in SOX-mediated transcriptional activity. Treatment of T-47D
breast cancer cells with the
synthetic progestin ORG 2058 directly increased SOX4 transcription, resulting in a 4-fold increase in SOX4
mRNA levels within 4 h of treatment. No effect of
ORG 2058 was noted on other SOX genes measured, nor were other
hormone-regulated
HMG box proteins detected in this system, suggesting that the observed ability of
progestin to increase SOX
mRNA expression was confined to SOX4. The increase in SOX4 transcription was reflected in increased SOX4
protein expression, as
progestin treatment of T-47D cells transfected with a SOX-responsive reporter resulted in a marked increase in reporter gene expression.
Progesterone is essential for normal development and differentiation of the female reproductive system, plays an essential role in regulating growth and differentiation of the mammary gland and is required for opposing the proliferative effects of
estrogen in specific cell types. The detection of SOX4 expression in the normal and malignant breast and the demonstration that SOX4 expression is under
progesterone control suggests that changes in SOX4 gene expression may play a role in commitment to the differentiated phenotype in the normal and malignant mammary gland.