We have previously reported that although SOX9 is a transcription factor, it is often localized in the cytoplasm of some invasive and metastatic breast carcinomas. To determine whether cytoplasmic compartmentalization is a common mechanism utilized by cancer cells to proliferate indefinitely, SOX9 localization was examined at different stages of development in normal mouse mammary glands and in cancer cells. We show here that SOX9 expression is nuclear in ductal epithelial cells throughout mammary gland development and differentiation but is localized in the cytoplasm of some breast cancer cell lines (BCCLs). Furthermore, cytoplasmic localization of SOX9 is associated with abrogation of the growth arrest response of breast cancer cells and results from dysregulated HDAC activity rather than defects in its nuclear export. Immuno-precipitation and immunoblot studies revealed that inhibiting HDAC activity with Trichostatin A can rescue this defect by up-regulating acetylated SOX9 and p21 expression that results in increased cell death. Our data suggests nuclear SOX9 expression parallels development and differentiation but cytoplasmic SOX9 expression is associated with abrogation of growth arrest response of breast cancer cells. Such expressions may be a common mechanism utilized by some transformed breast cancer cells to proliferate indefinitely.