Subcellular Localization of Total and Activated Src Kinase in African American and Caucasian Breast Cancer

Abstract

BackgroundSrc, a non-receptor tyrosine kinase is elevated in cancer with expression and activity correlated with cell proliferation, adhesion, survival, motility, metastasis and angiogenesis. There is limited data on Src expression and subcellular localization in breast cancer and no information about expression in racial/ethnic groups.Methodology/Principal FindingsThe present study evaluated Src expression, activity, and subcellular localization in triple negative breast cancer (TNBC) and ERα positive breast cancer (ER+BC), cancer tissue and adjacent normal epithelial ducts, and Caucasian and African American cases. 79 paraffin embedded breast carcinoma cases were obtained from Tulane University Hospital between 2007–2009. 39 cases represented TNBC (33-African Americans, 4-Caucasians, 2-unknowns) and 40 cases represented ER+BC (21-African Americans, 16-Caucasians, 3-unknowns). Immunohistochemistry was used to measure staining distribution and intensity of total Src and activated phospho-SrcY416 (p-Y416Src) in carcinoma tissue and adjacent normal mammary ducts. In TNBC and ER+BC, total Src was significantly higher in cancer compared to adjacent normal ducts (P<0.0001) in both cell membrane and cytoplasm. In membranes, p-Y416Src was elevated in cancer compared to normal ducts. Total Src in the tumor cytoplasm was significantly higher in TNBC compared to ER+BC (P = 0.0028); conversely, p-Y416Src in the tumor cell membranes was higher in TNBC compared to ER+BC (P = 0.0106). Comparison between African American (n = 21) and Caucasian ER+BC (n = 16) revealed no significant difference in expression and localization of total Src and p-Y416Src. TNBC cases positive for lymph node metastasis showed elevated membrane p-Y416Src compared to lymph node negative TNBC (P = 0.027).Conclusion/SignificanceTotal Src and p-Y416Src were expressed higher in cancer compared to adjacent normal ducts. Cytoplasmic total Src and membrane p-Y416Src were significantly higher in TNBC compared to ER+BC. TNBC cases with lymph node metastasis showed elevated membrane p-Y416Src. Taken together, Src was elevated in the membrane and cytoplasm of more aggressive TNBC.

UM-164: A Potent c-Src/p38 Kinase Inhibitor with In Vivo Activity against Triple-Negative Breast Cancer

“…S10, which shows that c-Src phosphorylation is nearly absent when MDA-MB 468 cells are treated with 50 nmol/L dasatinib. As in most TNBC cell lines (43,44), c-Src is membrane associated in MDA-MB 468 cells. We observed a profound change in c-Src localization upon treatment with UM-164, but no change in localization upon treatment with dasatinib (Fig.…”

Phosphatidylinositol Phosphate 5-Kinase Iγi2 in Association with Src Controls Anchorage-independent Growth of Tumor Cells

“…With these results, we have uncovered the mechanism of how focal adhesion molecules PIPKI␥i2, Src, and talin converge into a signaling complex to support oncogenic growth of tumor cells. This could be an oncogenic axis required for in vivo tumor growth and metastasis, including that of triple negative breast cancers, where PIPKI␥ and Src are predominantly overexpressed (23,49). Furthermore, the elucidation of oncogenic signaling molecules downstream of PIPKI␥i2 and Src and their functional relevance in vivo are future directions for study.…”

Fatty Acid Oxidation-Driven Src Links Mitochondrial Energy Reprogramming and Oncogenic Properties in Triple-Negative Breast Cancer

“…Aberrant Src activation plays prominent roles in cancer formation and progression (Aleshin and Finn, 2010; Finn, 2008; Mayer and Krop, 2010). The Src pathway is one of the most commonly upregulated pathways in TNBC (Anbalagan et al, 2012; Tryfonopoulos et al, 2011). While Src inhibitors hold promise in treating metastatic TNBC (Pal and Mortimer, 2009; Tryfonopoulos et al, 2011), initial clinical studies using Src inhibitor monotherapy in unselected patients with advanced BC showed only minor response (Finn et al, 2011; Gucalp et al, 2011; Herold et al, 2011; Mayer and Krop, 2010).…”