Somatic acquisition and signaling of TGFBR1*6A in cancer.
2005
ContextTGFBR1*6A is a common polymorphism of the type
I transforming growth factor β receptor (TGFBR1).
Epidemiological studies suggest that TGFBR1*6A may
act as a tumor susceptibility allele. How TGFBR1*6A
contributes to cancer development is largely unknown.ObjectivesTo determine whether TGFBR1*6A is somatically
acquired by primary tumors and metastases during cancer development and whether
the 3–amino acid deletion that differentiates TGFBR1*6A from TGFBR1 is part of the mature receptor
or part of the signal sequence and to investigate TGFBR1*6A signaling in cancer cells.Design, Setting, and PatientsTumor and germline tissues from 531 patients with a diagnosis of head
and neck, colorectal, or breast cancer recruited from 3 centers in the United
States and from 1 center in Spain from June 1, 1994, through June 30, 2004.
In vitro translation assays, MCF-7 breast cancer cells stably transfected
with TGFBR1*6A, TGFBR1, or the vector alone, DLD-1
colorectal cancer cells that endogenously carry TGFBR1*6A, and SW48 colorectal cancer cells that do not carry TGFBR1*6A.Main Outcome MeasuresTGFBR1*6A somatic acquisition in cancer. Determination
of the amino terminus of the mature TGFBR1*6A and TGFBR1 receptors. Determination
of TGF-β–dependent cell proliferation.ResultsTGFBR1*6A was somatically acquired in 13 of
44 (29.5%) colorectal cancer metastases, in 4 of 157 (2.5%) of colorectal
tumors, in 4 of 226 (1.8%) head and neck primary tumors, and in none of the
104 patients with breast cancer. TGFBR1*6A somatic
acquisition is not associated with loss of heterozygosity, microsatellite
instability, or a mutator phenotype. The signal sequences of TGFBR1 and TGFBR1*6A
are cleaved at the same site resulting in identical mature receptors. TGFBR1*6A may switch TGF-β growth inhibitory signals
into growth stimulatory signals in MCF-7 breast cancer cells and in DLD-1
colorectal cancer cells.ConclusionsTGFBR1*6A is somatically acquired in 29.5%
of liver metastases from colorectal cancer and may bestow cancer cells with
a growth advantage in the presence of TGF-β. The functional consequences
of this conversion appear to be mediated by the TGFBR1*6A signal sequence
rather than by the mature receptor. The results highlight a new facet of TGF-β
signaling in cancer and suggest that TGFBR1*6A may
represent a potential therapeutic target in cancer.
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