Protein tyrosine kinases (PTKs) play a critical role in the regulation of normal cell growth and differentiation; their overexpression may confer a growth advantage to breast cancer cells by increasing sensitivity to locally acting peptide growth factors, or by decreasing sensitivity to apoptotic signals. Elevated activity of membrane receptor PTKs occurs in a significant portion of breast tumors. Total soluble PTK activity in the cytosolic fractions of a majority of malignant human breast cancers is also higher than that from benign or normal breast tissue. Indeed, several novel non-receptor PTKs have recently been cloned from malignant human breast tissues and found to be highly active and/or overexpressed in a majority of breast cancers examined thus far. It is therefore important to define the role of these less well-characterized PTKs as novel components of known signaling pathways also overexpressed in a large proportion of human breast cancers. A novel nonreceptor PTK, termed breast tumor kinase (Brk) was cloned from a human metastatic breast tumor, and found to be overexpressed in human breast carcinomas and breast cancer cell lines, but not in normal adult breast tissue. Although clearly functionally distinct, Brk is closely related to c-Src, and contains one SH3-domain and one SH2-domain. In human breast cancer cells, Brk was activated in response to heregulin/c-erbB2 activation and Brk knock-down resulted in blockade of heregulin-induced ERK5 activation and cell proliferation. We hypothesize that Brk confers a growth and/or survival advantage to human breast cancer cells by acting as a signaling component downstream of erbB2/erbB3 receptor family members and upstream of ERK5, an emerging key regulator of cell growth, survival and transformation in mammary epithelial cells. Herein, we will 1) define the specificity and activity of a Brk-dependent signal transduction pathway to ERK5 activation in breast cancer cells 2) assay Brk-dependent alterations in cell biology and transformation in cells overexpressing Brk and during Brk gene-silencing, and 3) test the effects of Brk overexpression in the intact mammary gland in the context of heightened erbB2 signaling using transgenic mouse models. By identifying mechanisms underlying changes in growth factor receptor-mediated signaling events, we will increase the repertoire of regulatory proteins known to be involved in breast cancer cell growth and survival. Resistance to Herceptin is a frequent occurrence in patients with advanced breast cancer. Non- receptor PTK pathways acting downstream of erbB signaling may prove to be useful targets for chemotherapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA107547-02
Application #
7332287
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Jhappan, Chamelli
Project Start
2006-12-15
Project End
2011-11-30
Budget Start
2007-12-01
Budget End
2008-11-30
Support Year
2
Fiscal Year
2008
Total Cost
$249,357
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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Leehy, Katherine A; Regan Anderson, Tarah M; Daniel, Andrea R et al. (2016) Modifications to glucocorticoid and progesterone receptors alter cell fate in breast cancer. J Mol Endocrinol 56:R99-R114
Regan Anderson, Tarah M; Peacock, Danielle L; Daniel, Andrea R et al. (2013) Breast tumor kinase (Brk/PTK6) is a mediator of hypoxia-associated breast cancer progression. Cancer Res 73:5810-20
Locatelli, Alessia; Lofgren, Kristopher A; Daniel, Andrea R et al. (2012) Mechanisms of HGF/Met signaling to Brk and Sam68 in breast cancer progression. Horm Cancer 3:14-25
Lofgren, Kristopher A; Ostrander, Julie H; Housa, Daniel et al. (2011) Mammary gland specific expression of Brk/PTK6 promotes delayed involution and tumor formation associated with activation of p38 MAPK. Breast Cancer Res 13:R89
Locatelli, Alessia; Lange, Carol A (2011) Met receptors induce Sam68-dependent cell migration by activation of alternate extracellular signal-regulated kinase family members. J Biol Chem 286:21062-72
Castro, Nancy E; Lange, Carol A (2010) Breast tumor kinase and extracellular signal-regulated kinase 5 mediate Met receptor signaling to cell migration in breast cancer cells. Breast Cancer Res 12:R60
Ostrander, Julie H; Daniel, Andrea R; Lange, Carol A (2010) Brk/PTK6 signaling in normal and cancer cell models. Curr Opin Pharmacol 10:662-9
Ostrander, Julie Hanson; Daniel, Andrea R; Lofgren, Kristopher et al. (2007) Breast tumor kinase (protein tyrosine kinase 6) regulates heregulin-induced activation of ERK5 and p38 MAP kinases in breast cancer cells. Cancer Res 67:4199-209