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Protein kinase C isoform expression as a predictor of disease outcome on endocrine therapy in breast cancer

¹ CRUK Institute of Cancer Studies, University of Birmingham, Edgbaston, Birmingham, UK
² Tenovus Centre for Cancer Research, Welsh School of Pharmacy, Cardiff University, Cardiff, UK
³ Department of Histopathology, City Hospital, Nottingham, UK
⁴ Professional Unit of Surgery, City Hospital, Nottingham, UK

Correspondence to:
Dr J Assender, CRUK Institute of Cancer Studies, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK; J.W.Assender{at}bham.ac.uk

Background: Although in vitro breast cancer models have demonstrated a role for protein kinase C (PKC) and isoforms in endocrine insensitivity and resistance respectively, there is currently little clinical evidence to support these observations.

Aims: To define the pattern of PKC and expression using breast cancer cell lines, with and without endocrine resistance, and also breast cancer samples, where expression can be correlated with clinicopathological and endocrine therapy outcome data.

Methods: PKC isoform expression was examined in tamoxifen responsive, oestrogen receptor positive (ER⁺), ER⁺ acquired tamoxifen resistant (TAM-R) and oestrogen receptor negative (ER^–) cell lines by western blotting and immunocytochemical analysis. PKC isoform expression was then examined by immunohistochemistry in archival breast cancer specimens from primary breast cancer patients with known clinical outcome in relation to endocrine response and survival on therapy.

Results: ER⁺ breast cancer cell lines expressed considerable PKC- but barely detectable levels of PKC-, whereas ER^– cell lines expressed PKC- but little PKC-. ER⁺ acquired TAM-R cell lines expressed substantial levels of both PKC- and . In clinical samples, high PKC- expression correlated to endocrine responsiveness whereas PKC- expression correlated to ER negativity. PKC- was an independent predictor of duration of response to therapy. Patients showing a PKC-⁺/PKC-^– phenotype had a six times longer endocrine response than patients with the PKC-⁺/ PKC-⁺ phenotype (equating to tamoxifen resistance in vitro).

Conclusions: Levels of PKC- and expression appear to be indicative of response to anti-oestrogen therapy and could be useful in predicting a patient’s suitability for endocrine therapy.

Abbreviations: AP-1, activator protein-1 complex; BSA, bovine serum albumin; DAB, diamino benzidine-tetrahydrochloride; EGF, epidermal growth factor; ER, oestrogen receptor; ERK2, extracellular signal-regulated kinase 2; HR, hazard ratio; MAPK, mitogen activated protein kinase; NHS, normal human serum; PBS, phosphate buffered saline; PKC, protein kinase C; TAM-R, tamoxifen resistant; TBS, Tris buffered saline