Abstract
Protein tyrosine kinase 6 (PTK6, also called BRK) is an intracellular tyrosine kinase expressed in the majority of human breast tumors and breast cancer cell lines, but its expression has not been reported in normal mammary gland. To study functions of PTK6 in vivo, we generated and characterized several transgenic mouse lines with expression of human PTK6 under control of the mouse mammary tumor virus (MMTV) long terminal repeat. Ectopic active PTK6 was detected in luminal epithelial cells of mature transgenic mammary glands. Lines expressing the MMTV-PTK6 transgene exhibited more than a two-fold increase in mammary gland tumor formation compared with nontransgenic control animals. PTK6 activates signal transducer and activator of transcription 3 (STAT3), and active STAT3 was detected in PTK6-positive mammary gland epithelial cells. Endogenous mouse PTK6 was not detected in the normal mouse mammary gland, but it was induced in mouse mammary gland tumors of different origin, including spontaneous tumors that developed in control mice, and tumors that formed in PTK6, H-Ras, ERBB2 and PyMT transgenic models. MMTV-PTK6 and MMTV-ERBB2 transgenic mice were crossed to explore crosstalk between PTK6 and ERBB2 signaling in vivo. We found no significant increase in tumor incidence, size or metastasis in ERBB2/PTK6 double transgenic mice. Although we detected increased proliferation in ERBB2/PTK6 double transgenic tumors, an increase in apoptosis was also observed. MMTV-PTK6 clearly promotes mammary gland tumorigenesis in vivo, but its impact may be underrepresented in our transgenic models because of induction of endogenous PTK6 expression.
Highlights
In spite of recent advances, breast cancer remains the second leading cause of death for women in the United States.[1]
Induction of PTK6 in mouse mammary gland tumors of different origins M Peng et al 3 activation (P-Y705) was detected in individual tumors from PTK6 transgenic mice compared with tumors that developed in nontransgenic controls (Figure 5b)
We found that levels of active P-Y705 signal transducer and activator of transcription 3 (STAT3) correlated with expression of the PTK6 transgene (Figure 4, bottom panels)
Summary
In spite of recent advances, breast cancer remains the second leading cause of death for women in the United States.[1]. Protein tyrosine kinase 6 ( called breast tumor kinase or BRK) is a tyrosine kinase that promotes growth factor signaling, and proliferation, migration and survival of breast cancer cells (for reviews see[2,3,4,5,6]). It was identified in human metastatic breast cancer[7] and is overexpressed in the majority of human breast cancers and in most breast tumor cell lines.[8,9,10] Its expression in high grade ER( þ ) luminal B tumors was associated with poor outcomes.[11] The correlation between PTK6 and ERBB2 overexpression in invasive human ductal breast carcinomas[9,12,13,14] and the finding that PTK6 may cooperate with ERBB2 to promote breast tumor cell growth[14] raises the possibility that targeting. We examined potential synergy between PTK6 and ERBB2 signaling in mammary gland tumorigenesis and metastasis in vivo
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