Investigating the role of intracellular signaling pathways in regulating kallikrein expression Free

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Human tissue kallkreins (hKs) 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. The traditional understanding of hK activation involved the interaction of a hormone receptor with an upstream hormone response element (HRE), however the activation some hKs is more complicated and does not fall into this simple model. This study suggests that certain signal transduction pathways may influence regulation of both hormone-dependent and -independent hK gene expression. Two hormone-sensitive breast cancer cell lines, BT-474 and T-47D, and one hormone -independent cell line, MDA-MB-468, were chosen to study the involvement of two major intracellular signaling pathways, RAS/ERK and PI3K/AKT, in regulating kallikrein gene expression. Human kallikreins (hKs) hK10, 11, 13, and 14 are upregulated when BT-474 and T-47D are stimulated with estradiol and dihydrotestosterone (DHT), respectively. It was found that the expression of these hKs 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 hK gene activation. Furthermore, treating hormone-independent MDA-MB-468 cells with the PI3K inhibitor Wortmannin resulted in decreased expression of hK5 and hK6 but not hK10, implicating another signal transduction pathway in hK gene activation. We conclude that coordinated hormone-specific upregulation of kallikreins 10, 11, 13 and 14 and the dysregulated expression of hK5 and 6 in breast cancer cell lines likely involves signal transduction pathways such as RAS/ERK and PI3K.