PTK6 regulates growth and survival of endocrine therapy-resistant ER+ breast cancer cells. (December 2017) - Ito, Koichi
Abstract The non-receptor tyrosine kinase, PTK6/BRK, is highly expressed in multiple tumor types, including prostate, ovarian, and breast cancers, and regulates oncogenic phenotypes such as proliferation, migration, and survival. PTK6 inhibition also overcomes targeted therapy resistance of HER2+ breast cancer. Although PTK6 is highly expressed in ER+ Luminal breast cancers, the role of PTK6 in this subtype has not been elucidated. In this study, we investigated the functions of PTK6 in ER+ Luminal breast cancer cells, including those that are relatively resistant to estrogen deprivation or targeted endocrine therapies used in the treatment of ER+ cancers. Enhanced expression of PTK6 in ER+ breast cancer cells enhances growth of ER+ breast cancer cells, including tamoxifen-treated cells. Downregulation of PTK6 in ER+ breast cancer cells, including those resistant to tamoxifen, fulvestrant, and estrogen deprivation, induces apoptosis, as evidenced by increased levels of cleaved PARP, and an increase in the AnnexinV+ population. PTK6 downregulation impairs growth of these cells in 3D MatrigelTM cultures, and virtually abrogates primary tumor growth of both tamoxifen-sensitive and resistant MCF-7 xenografts. Finally, we show that p38 MAPK activation is critical for PTK6 downregulation-induced apoptosis, a mechanism that we previously reported for survival of HER2+ breast cancer cells, highlighting conserved mechanisms of survival regulation by PTK6 across breast cancer subtypes. In conclusion, our studies elucidate critical functions of PTK6 in ER+ Luminal breast cancers and support PTK6 as an attractive therapeutic target for ER+ breast cancers. Therapeutics: enzyme provides drug target for ER+ breast cancer Drugs that target a tumor-promoting enzyme called protein tyrosine kinase 6 (PTK6) could help treat hormone-receptor positive breast cancer. A team led by Hanna Irie from the Icahn School of Medicine at Mount Sinai in New York, NY, USA, investigated the role of PTK6, also known as breast tumor kinase, in breast cancer cells that grow in response to the hormone estrogen. They boosted the enzyme's expression in estrogen receptor-expressing breast cancer cells and saw enhanced growth. Conversely, downregulating PTK6 levels led to cell death, including in tumor cells that were resistant to tamoxifen and other therapies commonly used to treat estrogen-receptor positive breast cancer. The researchers showed that this effect was dependent on the activation of a signaling pathway previously found to be important in another subtype of breast cancer, highlighting a conserved mechanism of cell survival regulation by PTK6.