14-3-3 Proteins in Normal and Tumour Cell Biology - Therapeutic Strategies in Cancer Biology and Pathology - page 80

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14-3-3 Proteins in Normal and
Tumour Cell Biology

The 14-3-3 proteins are ubiquitously expressed in many normal tissues and have
been associated with cell signalling systems, cell proliferation, cell cycle regula-
tion and apoptosis, cytoskeletal dynamics, to name those cellular functions crucial
in tumour development and dissemination. Their wide ranging function can be attrib-
uted to the numerous interacting proteins that interact with 14-3-3s. Several iso-
forms of 14-3-3 have been identified, seven β, γ, ϵ, ζ, η, σ and τ encoded by seven
genes in mammals. These appear to display much diversity of phenotypic outcome
ascribable with no uncertainty to the gamut of their targets. Some are tumour sup-
pressors and others promoters. The inclusion of the discussion of this protein fam-
ily with tumour suppressors is therefore merely a matter of expediency. The 14-3-3s
operate by binding to phosphorylated-serine/threonine motifs on their target proteins
and modulate their function. In doing so they effectively modulate several signalling
pathways to generate positive or negative regulation of cell motility and invasion,
cell proliferation and apoptosis, EMT and metastasis (see Neal and Yu, 2010, for a
highly erudite review). The ability of 14-3-3 to complex with and function as scaf-
fold protein affects subcellular localisation of the targets. This faculty of 14-3-3 has
been exploited as a therapeutic tool.

Expression of 14-3-3 σ in Tumour Progression

The 14-3-3 proteins are differentially expressed in tumours. The isoform 14-3-3σ, an
epithelial marker, is the most attributed with tumour suppressor ability on account
of its downregulated expression by promoter methylation in many tumours. Early
work on breast cancer revealed that the expression of 14-3-3σ decreased from
92% in breast ductal hyperplasia to 65% in ductal carcinoma in situ and further
down to 23% in invasive ductal carcinoma (Simooka et al., 2004). This downreg-
ulation occurs by promoter methylation and this has been encountered in around
9/10 patients as compared with about a fifth of hyperplastic tissue and none being
found in normal breast tissue (Luo et al., 2010). But this is not in agreement with
the early effort of Moreira et al. (2005) who found equivalent levels of 14-3-3σ in
non-malignant and malignant breast cancer and only 3/68 tumours showed loss of
its expression. Albeit in samples from a small number of patients, Li et al. (2009b)
found that14-3-3σ was downregulated in metastatic lesions of squamous cell carci-
noma of the lung, suggesting cell subpopulations expressing low levels of 14-3-3σ
might possess a greater ability or propensity to form metastases. They transfected