Editors' ChoiceCancer Biology

Patched Polymorphisms in Skin Cancer

Science's STKE  20 Feb 2007:
Vol. 2007, Issue 374, pp. tw60
DOI: 10.1126/stke.3742007tw60

Activation of the sonic hedgehog (SHH) pathway has been implicated in basal cell carcinoma (BCC), and one mechanism to achieve aberrant SHH signaling is through loss of the function of Patched (Ptch, also sometimes abbreviated Ptc), a receptor that inhibits the pathway in the absence of SHH. Wakabayashi et al. now implicate aberrant Ptc function in susceptibility to squamous cell carcinoma (SCC) caused by H-Ras. They mapped the difference in susceptibility of two strains of mice to H-Ras-induced SCC: C57BL/6 mice are resistant to SCC, and FVB/N mice are susceptible to SCC compared with a control mouse strain. They found a polymorphism in the Ptch gene that resulted in the appearance of either a Thr (resistant mice PtchB6) or an Asn (susceptible mice PtchFVB) at position 1267 in the C-terminal region. Comparison with the human protein revealed that humans have an Asn in that position. This polymorphism affected the interaction of Ptch with Tid1, with the PtchB6 version interacting with the short form of this protein, which has been implicated in Ras-induced apoptosis and senescence. In contrast, PtchFVB did not interact with Tid1 by coimmunoprecipitation when expressed in transfected cells. When coexpressed in NIH 3T3 cells or C5N keratinocytes with H-Ras, only the PtcFVB inhibited apoptosis. In mice transgenic for PtcFVB in the skin, Ptc and Gli transcripts were present in normal skin, whereas these two transcripts were repressed in the SCC tumors. This implies that the altered Ptch function may be required at a very early stage in tumor initiation but is not required or is actively silenced in the tumors. This contrasts with the situation in BCC in which increased SHH signaling is present. The authors propose a mechanism for SHH in cell fate determination that may contribute to the two different forms of cancer, with Ptch activity contributing to SCC and Ptch loss contributing to BCC.

Y. Wakabayashi, J.-H. Mao, K. Brown, M. Girardi, A. Balmain, Promotion of Hras-induced squamous carcinomas by a polymorphic variant of the Patched gene in FVB mice. Nature 445, 761-765 (2007). [PubMed]