title: Phosphorylated c-Src in the nucleus is associated with improved patient outcome in ER-positive breast cancer.
abstract: Elevated c-Src protein expression has been shown in breast cancer and in vitro evidence suggests a role in endocrine resistance. To investigate whether c-Src is involved in endocrine resistance, we examined the expression of both total and activated c-Src in human breast cancer specimens from a cohort of oestrogen receptor (ER)-positive tamoxifen-treated breast cancer patients. Tissue microarray technology was employed to analyse 262 tumour specimens taken before tamoxifen treatment. Immunohistochemistry using total c-Src and activated c-Src antibodies was performed. Kaplan-Meier survival curves were constructed and log-rank test were performed. High level of nuclear activated Src was significantly associated with improved overall survival (P=0.047) and lower recurrence rates on tamoxifen (P=0.02). Improved patient outcome was only seen with activated Src in the nucleus. Nuclear activated Src expression was significantly associated with node-negative disease and a lower NPI (P<0.05). On subgroup analysis, only ER-positive/progesterone receptor (PgR)-positive tumours were associated with improved survival (P=0.004). This shows that c-Src activity is increased in breast cancer and that activated Src within the nucleus of ER-positive tumours predicts an improved outcome. In ER/PgR-positive disease, activated Src kinase does not appear to be involved in de novo endocrine resistance. Further study is required in ER-negative breast cancer as this may represent a cohort in which it is associated with poor outcome.
authors.affiliation: Division of Cancer Sciences and Molecular Pathology, Department of Surgery, Glasgow Royal Infirmary, Glasgow, UK.
authors.forename: E J
authors.initials: EJ
authors.lastname: Campbell
authors.forename: E
authors.initials: E
authors.lastname: McDuff
authors.forename: O
authors.initials: O
authors.lastname: Tatarov
authors.forename: S
authors.initials: S
authors.lastname: Tovey
authors.forename: V
authors.initials: V
authors.lastname: Brunton
authors.forename: T G
authors.initials: TG
authors.lastname: Cooke
authors.forename: J
authors.initials: J
authors.lastname: Edwards
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality*; D000081247:CSK Tyrosine-Protein Kinase; D002467:Cell Nucleus / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality*; D010766:Phosphorylation; D011379:Prognosis; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D013629:Tamoxifen / Q000627:therapeutic use; D046888:Tissue Array Analysis; D019061:src-Family Kinases
chemical_list: D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D004967:Estrogens; D011518:Proto-Oncogene Proteins; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D013629:Tamoxifen; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human