The Role of Protein Tyrosine Kinase 6 in the Mammary Gland Epithelium and Breast Cancer
thesisposted on 20.06.2014, 00:00 by Maoyu Peng
Breast cancer is the second leading cause of cancer-related death in women in US. A non-receptor tyrosine kinase named Protein Tyrosine Kinase 6 (PTK6) has been identified in the majority of human breast cancers, but the roles of PTK6 in breast tumorigenesis was unclear. In this thesis, we studied the functions of PTK6 in normal mammary glands and in breast tumors. PTK6 was not detected in normal human mammary gland previously, but we discovered PTK6 expression in the mammary gland epithelial cells of all the patient samples we studied, and PTK6 may be playing kinase independent roles because it was not active. In contrast, we discovered that PTK6 was often activated in high grade human breast tumors. PTK6 is not expressed in normal mouse mammary gland. We generated transgenic mouse that expressed human PTK6 in the mammary glands, and we detected a 2.4-fold increase in breast tumor formation in all the transgenic lines. In the mammary glands and the breast tumors from transgenic animals, we detected constitutive activation of ectopic PTK6 and STAT3, a PTK6 substrates that regulates pro-survival signaling. STAT3 activation may have contributed to increased breast tumor formation. ERBB2 (B2) is a known breast tumor oncogene. To study the synergistic effect of PTK6 and B2 on breast tumorigenesis, we crossed the PTK6 mice with the B2 mice. A higher proliferation rate was observed in B2/PTK6 tumors but it was counteracted by increased apoptosis. In addition, endogenous mouse PTK6 was induced in both B2 and B2/PTK6 tumors and may have partially masked the effect of ectopic human PTK6. To evaluate the importance of endogenous mouse PTK6 induction, we crossed B2 mice with Ptk6 null (Ptk6-/-) mice, and observed a significant delay in breast tumor initiation. We found that proliferation rates of mammary gland epithelium were much lower in B2, Ptk6-/- mice. Also, levels of activated FAK and p130Cas, two PTK6 substrates that play roles in cell migration, were decreased in B2, Ptk6 -/- tumors, suggesting that disrupting PTK6 expression may decrease the metastasis potential of breast tumors. In addition, we found out that knockdown of PTK6 increased trastuzumab-induced growth inhibition in ERBB2 overexpressing cell line and sensitized breast cancer cells to chemotherapy and irradiation treatment.