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.
Highlights
70% of all diagnosed breast cancers express estrogen receptor (ER) and/or progesterone receptor (PR) and are stimulated to grow in the presence of estrogen
We reported that protein tyrosine kinase 6 (PTK6) downregulation impaired the growth of several lapatinib-resistant HER2+ breast cancer cell lines and induced apoptosis by enhancing Bim expression.[25]
While many patients with ER and/or PR-positive tumors are successfully treated with these therapies, some experience recurrences even several years after their initial diagnosis, indicative of intrinsic or acquired resistance
Summary
70% of all diagnosed breast cancers express estrogen receptor (ER) and/or progesterone receptor (PR) and are stimulated to grow in the presence of estrogen. We report on the role of protein tyrosine kinase 6 (PTK6) in survival and growth of ER+ Luminal breast cancer cells, including those resistant to standard endocrine therapies used in the treatment of patients with ER+ breast cancers. Higher PTK6 transcript expression in patient tumors is associated with adverse outcomes.[19] increased expression of PTK6 in MCF-10A breast epithelial cells was sufficient to confer resistance to the growth inhibitory effects of treatment with lapatinib, a clinically used small molecule inhibitor of HER1/2 kinases.[24] we reported that PTK6 downregulation impaired the growth of several lapatinib-resistant HER2+ breast cancer cell lines and induced apoptosis by enhancing Bim expression.[25]. Given the growing evidence for a critical role for PTK6 in breast (Supplemental Fig. 1) Based on these in silico results, we cancer cell survival, we sought to determine the functional role of investigated the role of PTK6 in promoting the growth of ER+. Breast cancer cells, we overexpressed active PTK6 (MF-PTK6) in ER + MCF-7 and T47D breast cancer cell lines, which are relatively
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