Human tissue kallkreins (KLKs) in breast cancer cell lines show both hormone-dependent and independent expression, however the regulatory pathways which ultimately lead to gene activation have not been dissected. This study suggests that certain signal transduction pathways may influence regulation of both hormone-dependent and independent KLK gene expression. Two hormone-sensitive breast cancer cell lines, BT474 and T47D, and one hormone -independent cell line, MDA-MB-468, were chosen to study the involvement of the intracellular signaling pathways in regulating kallikrein gene expression. PSA is upregulated upon androgen stimulation in both T47D and BT474 cell lines, whereas KLK10 and KLK11 are upregulated when BT-474 and T-47D are stimulated with estradiol and dihydrotestosterone (DHT), respectively. The expression of these KLKs was repressed by the MEK1/2 inhibitor U0126 in the presence of the hormone, thus implicating the RAS/ERK signaling pathway in regulating hormone-dependent KLK gene activation. Furthermore, treatment with the PI3K inhibitor Wortmannin also resulted in decreased expression of these kallikreins in the presence of the respective hormones. However, selective chemical inhibitors against JNK, p38 MAPK, JAK, NFκB, and GSK3β pathways showed differential regulation of the above KLKs, with PSA and KLK11 showing parallel regulation patterns versus KLK10. KLK5 and KLK6, whose expression is independent of hormone activity in MDA-MB-468 cells, also showed differential selectivity in their regulation upon inhibitor treatments. Furthermore, analysis of inhibitor-treated cells for changes in transcription factor expression showed that some factors were altered in a pattern parallel to kallikrein expression. We conclude that the hormone-specific upregulation of PSA, KLK10 and KLK11 and the dysregulated expression of KLK5 and KLK6 in breast cancer cell lines are dependent on major intracellular signaling pathways, as well as specific transcription factors, providing a new dimension to the regulation of these cancer-related genes.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA