Constitutive activation of breast tumor kinase accelerates cell migration and tumor growth in vivo

Abstract

Breast tumor kinase (BRK) is a non-receptor tyrosine kinase overexpressed in most human breast tumors, including lymph node metastases, but undetected in normal mammary tissue or in fibroadenomas. The activity of BRK-like Src family tyrosine kinase, is regulated negatively by phosphorylation of C-terminal tyrosine 447. Although the kinase that regulates BRK activation has not been identified, we and others have previously shown that BRK-Y447F is a constitutively active variant. Because BRK-Y447F significantly enhances the catalytic activity of the enzyme, we investigated the role of the constitutively active BRK variant in tumor formation and metastasis. Using stable breast cancer cell MDA-MB-231 we observed significantly enhanced rates of cell proliferation, migration and tumor formation in BRK-Y447F stable cells compared with wild-type stable cell lines. Our results indicate full activation of BRK is an essential component in the tumorigenic role of BRK.

BRK Phosphorylates SMAD4 for proteasomal degradation and inhibits tumor suppressor FRK to control SNAIL, SLUG and metastatic potential

“…Consistent with this, BRK has been shown to promote HER2-induced tumorigenesis in orthotropic transplantation-based models (10). We have also reported that BRK activation significantly enhances tumor formation in xenograft models (5). Additionally, BRK is overexpressed in over 80% of breast carcinomas (1), and in many other major cancer types including lung (11), ovarian (12), and pancreatic (13) cancers.…”

“…It is composed of an Src homology 3 domain (SH3 domain), an SH2 domain, and a catalytic tyrosine kinase domain (3). Like Src, BRK is negatively regulated by phosphorylation of its C-terminal tyrosine 447 and activated by phosphorylation of tyrosine 342 in the catalytic domain 4,5 . Mutation of tyrosine 447 to phenylalanine significantly enhances the kinase activity of BRK(4) , (5).…”

BRK Targets Dok1 for Ubiquitin-Mediated Proteasomal Degradation to Promote Cell Proliferation and Migration

“…We recently showed that constitutive activation of BRK promotes cell proliferation and migration as well as tumor formation, validating the proto-oncogenic function of BRK [28]. ; however, the molecular mechanisms dictating the tumorigenic role of BRK are poorly understood.…”

“…Ectopic expression of Dok1 has been shown to inhibit cell proliferation and transformation induced by oncogenic tyrosine kinases, including the p210 bcr-abl and Src family kinases [57], [60]. Previously, we along with others showed that BRK overexpression and activation enhanced cell proliferation, cell migration and tumor formation [26], [28], [33], [61], [62], [63]. To test whether Dok1 can also modulate the oncogenic properties of BRK, we evaluated the effect of Dok1 on BRK-induced cell proliferation and migration.…”

Evolution of breast cancer therapeutics: Breast tumour kinase’s role in breast cancer and hope for breast tumour kinase targeted therapy

“…Activation of STAT3 by Brk may contribute towards cell transformation and uncontrolled growth in early stages of breast cancer. Brk also mediates STAT3 regulation in established tumours [80] , and constitutive activation of Brk accelerated cell migration and tumour growth in vivo [82] . Angiogenesis has been recognised as an essential process in survival of cancerous cells in vivo; it is involved in tumour growth, progression and metastasis [83] .…”