Imaging tumour heterogeneity of the consequences of a PKCα-substrate interaction in breast cancer patients.
Breast cancer heterogeneity demands that prognostic models must be biologically driven and recent clinical evidence indicates that future prognostic signatures need evaluation in the context of early compared with late metastatic risk prediction. In pre-clinical studies, we and others have shown that various protein-protein interactions, pertaining to the actin microfilament-associated proteins, ezrin and cofilin, mediate breast cancer cell migration, a prerequisite for cancer metastasis. Moreover, as a direct substrate for protein kinase Cα, ezrin has been shown to be a determinant of cancer metastasis for a variety of tumour types, besides breast cancer; and has been described as a pivotal regulator of metastasis by linking the plasma membrane to the actin cytoskeleton. In the present article, we demonstrate that our tissue imaging-derived parameters that pertain to or are a consequence of the PKC-ezrin interaction can be used for breast cancer prognostication, with inter-cohort reproducibility. The application of fluorescence lifetime imaging microscopy (FLIM) in formalin-fixed paraffin-embedded patient samples to probe protein proximity within the typically <10 nm range to address the oncological challenge of tumour heterogeneity, is discussed.
*Richard Dimbleby Department of Cancer Research, Randall Division & Division of Cancer Studies, Kings College London, Guy's Medical School Campus, London SE1 1UL, U.K.
Gregory
G
Weitsman
Katherine
K
Lawler
Muireann T
MT
Kelleher
†Department of Mathematics, King's College London, Strand Campus, London WC2R 2LS, U.K.
James E
JE
Barrett
§Gray Institute for Radiation Oncology & Biology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.
Paul R
PR
Barber
*Richard Dimbleby Department of Cancer Research, Randall Division & Division of Cancer Studies, Kings College London, Guy's Medical School Campus, London SE1 1UL, U.K.
Eamon
E
Shamil
║Biomaterials, Biomimetics and Biophotonics Division, King's College London Dental Institute, London SE1 9RT, U.K.
Frederic
F
Festy
Gargi
G
Patel
Gilbert O
GO
Fruhwirth
§Gray Institute for Radiation Oncology & Biology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.
Lufei
L
Huang
§Gray Institute for Radiation Oncology & Biology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.
Iain D C
ID
Tullis
††Guy's & St. Thomas' Breast Tissue & Data Bank, King's College London, Guy's Hospital, London SE1 9RT, U.K.
Natalie
N
Woodman
*Richard Dimbleby Department of Cancer Research, Randall Division & Division of Cancer Studies, Kings College London, Guy's Medical School Campus, London SE1 1UL, U.K.
Enyinnaya
E
Ofo
*Richard Dimbleby Department of Cancer Research, Randall Division & Division of Cancer Studies, Kings College London, Guy's Medical School Campus, London SE1 1UL, U.K.
Simon M
SM
Ameer-Beg
‡‡Breakthrough Breast Cancer Research Unit, Department of Research Oncology, Guy's Hospital King's College London School of Medicine, London, SE1 9RT, U.K.
Sheeba
S
Irshad
§§Tumor Microenvironment and Metastasis Program, Albert Einstein Cancer Center, New York, NY 10461, U.S.A.
John
J
Condeelis
††Guy's & St. Thomas' Breast Tissue & Data Bank, King's College London, Guy's Hospital, London SE1 9RT, U.K.
Cheryl E
CE
Gillett
¶Department of Medical Oncology, Guy's and St. Thomas Foundation Trust, London SE1 9RT, U.K.
Paul A
PA
Ellis
Borivoj
B
Vojnovic
†Department of Mathematics, King's College London, Strand Campus, London WC2R 2LS, U.K.
Anthony C C
AC
Coolen
Tony
T
Ng
D051339:Actin Depolymerizing Factors / Q000378:metabolism; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D005260:Female; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D051571:Protein Kinase C-alpha / Q000378:metabolism*; D013347:Subcellular Fractions / Q000378:metabolism; D013379:Substrate Specificity; D016896:Treatment Outcome; D000099149:Ezrin
D051339:Actin Depolymerizing Factors; D003598:Cytoskeletal Proteins; D051571:Protein Kinase C-alpha; D000099149:Ezrin