Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2009 Oct 7.
Published in final edited form as: J Invest Dermatol. 2009 Apr 2;129(9):2109–2112. doi: 10.1038/jid.2009.79

PTEN: New Insights into Its Regulation and Function in Skin Cancer

Mei Ming 1, Yu-Ying He 1
PMCID: PMC2758921  NIHMSID: NIHMS130379  PMID: 19340009

Abstract

Skin cancer is the most common cancer in the United States. UV radiation in sunlight is the major environmental factor causing skin cancer development. PTEN (phosphatase and tensin homolog deleted on chromosome 10), a recently discovered tumor suppressor gene, is frequently mutated, deleted, or epigenetically silenced in various human cancers. PTEN negatively regulates the oncogenic phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathways. PTEN is clearly a critical tumor suppressor for skin cancer in humans and in mice. This review summarizes the recent progress in the function of PTEN in the development of skin cancer, including basal-cell carcinoma, squamous-cell carcinoma, and melanoma. The regulation of PTEN by UV radiation is also discussed in association with skin carcinogenesis. Understanding the fundamental mechanisms that lead to the reduction of PTEN function in skin carcinogenesis and the essential association with UV radiation opens up new opportunities for molecular chemoprevention and therapy of skin cancer by targeting PTEN pathways.

INTRODUCTION

Skin cancer is the most common type of cancer in the United States. Each year more than one million new cases are diagnosed, accounting for more than 40% of all cancers diagnosed. Skin cancers include basal-cell carcinoma (BCC), squamous-cell carcinoma (SCC), known as non-melanoma skin cancer, and melanoma. BCCs and SCCs account for ~80 and 16% of all skin cancers, respectively, whereas malignant melanomas account for only 4% of all skin cancers (Bowden, 2004). BCCs and SCCs are both derived from the basal layer of the epidermis of the skin. BCCs are slow growing and rarely metastasize, whereas SCCs can be highly invasive and may metastasize (Bowden, 2004). In contrast, melanoma is derived from melanocytes and the mortality associated with melanoma is high. UV irradiation in sunlight (Ramos et al., 2004; Erb et al., 2008) is the major environmental factor causing skin cancer. The rising incidence rates of BCC, SCC, and melanoma are highly associated with increased exposure to UV radiation because of increased sun exposure caused by sunbed tanning for cosmetic purposes, increased outdoor activities, changes in clothing style, increased longevity, and/or ozone depletion (Rigel, 2008).

PTEN (phosphatase and tensin homolog deleted on chromosome 10) functions as a highly effective tumor suppressor in a wide variety of tumor tissues (Suzuki et al., 2008) by negatively regulating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway (Maehama and Dixon, 1998). Loss of PTEN function through deletion, mutation, and/or decreased expression, has been found both in human sporadic cancers (Steck et al., 1997; Kohno et al., 1998; Birck et al., 2000; Harima et al., 2001; Byun et al., 2003) and in hereditary cancer syndromes (Liaw et al., 1997; Marsh et al., 1997; Harima et al., 2001). This ubiquitous and evolutionarily conserved signaling cascade influences many functions, including cell growth, survival, proliferation, migration, and metabolism (Endersby and Baker, 2008). Although largely unknown, similar or distinct PTEN involvement may exist in skin carcinogenesis.

The review here is to provide a new perspective of PTEN regulation and function in skin carcinogenesis, its interaction with other critical signaling pathways involved in skin cancer, and its regulation by environmental UV radiation. Furthermore, the possibility of selectively targeting PTEN chemoprevention and therapy of skin cancer is also discussed.

PTEN IN SKIN CANCER

Functional studies supported the hypothesis that PTEN is a critical tumor suppressor in skin cancer. Loss of PTEN activity through mutation, deletion, or reduced expression has been shown to play an important role in skin tumor development. Germline mutations in PTEN, detected in patients with Cowden’s disease and Bannayan–Riley–Ruvalcaba syndrome (Bonneau and Longy, 2000), lead to the loss of PTEN function, which increases the risk of tumorigenesis in skin as well as in other organs (Liaw et al., 1997; Trojan et al., 2001).

PTEN in BCC

Loss of PTEN function may be critical for BCC formation through activating Sonic Hedgehog (Shh) signaling. BCC, at the molecular level, is characterized by aberrant activation of Shh signaling, usually because of mutations either in the patched (Ptc) or smoothened (Smo) genes (Reifenberger, 2007), or because of hyperactivation of this pathway. It is interesting that PTEN may be critical for Shh signaling. Recent studies have shown that PI3K/AKT activation is essential for Shh signaling by controlling PKA-mediated Gli inactivation (Riobo et al., 2006). Although little is known regarding PTEN function in BCC, loss of PTEN function in BCC would upregulate the PI3K/AKT pathway to stimulate even low-level ligand-dependent or ligand-independent Shh signaling caused by mutations in Hedgehog pathway components. Although deletions of 10q23, where PTEN is located, were found to be an infrequent event in BCC (Quinn et al., 1994), the inactivation of PTEN by other mechanisms may play an important role in BCC development.

PTEN in SCC

The critical role of genetic PTEN suppression in SCC has been shown in humans and in mice. The tumor suppressing function of PTEN in SCC has been shown in patients with Cowden’s disease, in vitro in human keratinocytes, and in vivo, using a chemical skin carcinogenesis model. The association of cutaneous SCC with Cowden’s disease has also been reported (Nuss et al., 1978; Camisa et al., 1984). The decreasing levels of PTEN expression are correlated with a malignant transformation of the skin induced by UVA (315–400 nm), as shown by the formation of SCC in nude mice (He et al., 2006).

Mice with PTEN deletion and mutation are highly susceptible to tumor induction (Suzuki et al., 1998). Conditional knockout of PTEN in skin leads to neoplasia in skin (Li et al., 2002; Suzuki et al., 2003; Backman et al., 2004), thereby showing the pivotal role of PTEN in skin cancer development. PTEN deficiency in mice causes increases in cell proliferation, apoptotic resistance, stem-cell renewal/maintenance, centromeric instability, and DNA double-strand breaks (Groszer et al., 2001; Kimura et al., 2003; Wang et al., 2006; He et al., 2007; Shen et al., 2007; Yanagi et al., 2007), which can enhance susceptibility to carcinogens and the occurrence of secondary genetic or epigenetic alterations that can lead to skin cancer development.

Complex mechanisms may mediate the inactivation of PTEN. Somatic mutations, deletion, or promoter hypermethylation of PTEN have not been detected in SCCs of human skin (Quinn et al., 1994; Kubo et al., 1999; Murao et al., 2006). Thus, the inactivation of PTEN by other mechanisms may be involved in SCC pathogenesis, including inactivation of the protein and/or epigenetic silencing, and the mechanism(s) by which its function and activity are regulated remain to be established.

Loss of PTEN function may occur as an early or late event, and PTEN loss has contributed to skin cancer development. Immunohistochemical studies have shown that, in mouse skin tumors, PTEN immunoreactivity was clearly confined to differentiating areas of the papillomas, and to the most differentiating areas in SCC samples, whereas PTEN staining is lost in non-differentiating infiltrative areas of SCCs, suggesting the expression and localization of PTEN in tumor sections that represent the different stages of mouse skin carcinogenesis (Segrelles et al., 2002).

PTEN in melanoma

Loss of PTEN function has been implicated in the development of melanoma (Wu et al., 2003). A high frequency of PTEN mutations has also been detected in malignant melanomas (Bonneau and Longy, 2000). On the basis of melanoma cell lines and mainly metastatic tumors, many studies also showed that PTEN played a significant role in sporadic cutaneous melanomas (Tsao et al., 1998). PTEN inactivation was a late event likely related to melanoma progression rather than to initiation, and the translocation of PTEN expression from nuclear predominance to cytoplasmic predominance occurs from melanocyte to primary melanoma to metastasis melanoma. The potential genetic interaction among NRAS, BRAF, and PTEN may play a critical role in melanoma development (Tsao et al., 2004).

Loss of PTEN function also increases AKT3 activation in melanoma. AKT3 protein, but not AKT1 or AKT2 protein, was found to be increased in melanoma cell lines when compared with normal melanocytes. Mechanisms of AKT3 deregulation occurred through a combination of overexpression of AKT3, accompanying copy number increases of the gene, and decreased PTEN protein function, occurring through loss or haploinsufficiency of the PTEN gene (Stahl et al., 2004; Robertson, 2005).

PTEN REGULATION BY UV RADIATION

Recent studies show that UV radiation regulates PTEN function in skin cells. UV exposure causes gene alteration of PTEN (Hocker and Tsao, 2007). Inducing Egr-1 by exposing cells to acute UVC (100–280 nm) upregulates the expression of the PTEN messenger RNA and protein, and leads to apoptosis. Loss of Egr-1 expression, which often occurs in human cancers, could deregulate the PTEN gene and contribute to the radiation resistance of some cancer cells (Virolle et al., 2001).

Our recent evidence shows that chronic UVA radiation decreased PTEN expression, and this decrease is required for enhanced cell survival in the transformed human keratinocytes, suggesting that PTEN might be critical for skin carcinogenesis induced by UVA (He et al., 2006). PTEN increases sensitivity to cell death in response to several apoptotic stimuli, including UV irradiation and treatment with tumor necrosis factor α, by negatively regulating the PI3K/AKT pathway (Stambolic et al., 1998), implying that PTEN alterations might be involved in UV-induced skin cancer. UVB (280–315 nm) was also reported to inhibit PTEN by increasing PTEN phosphorylation in human dermal fibroblasts, as phosphorylation of PTEN downregulates its lipid phosphatase and protein stability (Oh et al., 2006). Thus UV-mediated inhibition of PTEN function may further enhance AKT activation induced by UV radiation.

It is likely that multiple complex interactions at the transcriptional, post-transcriptional, and/or post-translational levels are involved. Systematic characterization of PTEN regulation by UV radiation will not only advance our knowledge of the fundamental mechanisms of PTEN involvement in skin cancer, but also facilitate the development of feasible approaches to prevent PTEN suppression because of chronic UV exposure.

Furthermore, UV-induced production of reactive oxygen species and the resultant oxidative stress exposure plays an important role in photocarcinogenesis caused by UV, and reactive oxygen species are believed to be involved in many inflammatory skin disorders, skin cancer formation, phototoxicity, and skin aging. PTEN activity can be inhibited by reactive oxygen species (Gimm et al., 2000), implying that reduced PTEN activity by UV-induced reactive oxygen species formation might be involved in UV-induced skin tumorigenesis.

CONCLUSIONS AND FUTURE DIRECTIONS

PTEN plays a critical role in skin homeostasis and is a critical tumor suppressor in the prevention of skin carcinogenesis, as shown in humans and in mice. This has positioned PTEN in a central role of tumor suppression by antagonizing PI3K/AKT pathways in skin carcinogenesis. Proper function of PTEN is essential for maintaining the balance in cell proliferation and survival in epidermal cells, including keratinocytes and melanocytes in skin, to prevent transformation.

In addition, UV radiation, the major risk factor causing skin cancer, suppresses PTEN expression, indicating that PTEN may be the critical target for UV-induced skin tumorigenesis. As skin cancer is the most common malignancy in the United States, elucidating the mechanisms of PTEN function, and its regulation and function in the pathogenesis of BCC, SCC, and melanoma will have a broad impact in improving patients' quality of life and reduce the high morbidity associated with these cancers. Targeted PTEN, directly or by interfering with upstream proteins regulating PTEN activity, presents a new and more effective preventive and therapeutic approach in reducing skin cancer burden, as suggested in other cancers. Recently, the protective nature of phytoestrogens has been shown to be partially mediated by increasing PTEN expression, indicating that PTEN may be one of the critical molecular targets for skin cancer prevention and treatment.

ACKNOWLEDGMENTS

We apologize to those investigators whose work could not be directly referenced owing to space limitations. Work in the authors' laboratory was supported by the Department of Medicine and the Section of Dermatology at the University of Chicago, the American Skin Association, and the University of Chicago Cancer Research Center (P30 CA014599). The authors are grateful for Dr Ann Motten for her critical reading of this manuscript.

Abbreviations

AKT

protein kinase B

BCC

basal-cell carcinoma

PI3K

phosphoinositide 3-kinase

PTEN

phosphatase and tensin homolog deleted on chromosome 10

SCC

squamous-cell carcinoma

Shh

sonic Hedgehog

Footnotes

CONFLICT OF INTEREST

The authors state no conflict of interest.

REFERENCES

  1. Backman SA, Ghazarian D, So K, Sanchez O, Wagner KU, Hennighausen L, et al. Early onset of neoplasia in the prostate and skin of mice with tissue-specific deletion of Pten. Proc Natl Acad Sci USA. 2004;101:1725–1730. doi: 10.1073/pnas.0308217100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Birck A, Ahrenkiel V, Zeuthen J, Hou-Jensen K, Guldberg P. Mutation and allelic loss of the PTEN/MMAC1 gene in primary and metastatic melanoma biopsies. J Invest Dermatol. 2000;114:277–280. doi: 10.1046/j.1523-1747.2000.00877.x. [DOI] [PubMed] [Google Scholar]
  3. Bonneau D, Longy M. Mutations of the human PTEN gene. Hum Mutat. 2000;16:109–122. doi: 10.1002/1098-1004(200008)16:2<109::AID-HUMU3>3.0.CO;2-0. [DOI] [PubMed] [Google Scholar]
  4. Bowden GT. Prevention of non-melanoma skin cancer by targeting ultraviolet-B-light signalling. Nat Rev Cancer. 2004;4:23–35. doi: 10.1038/nrc1253. [DOI] [PubMed] [Google Scholar]
  5. Byun DS, Cho K, Ryu BK, Lee MG, Park JI, Chae KS, et al. Frequent monoallelic deletion of PTEN and its reciprocal associatioin with PIK3CA amplification in gastric carcinoma. Int J Cancer. 2003;104:318–327. doi: 10.1002/ijc.10962. [DOI] [PubMed] [Google Scholar]
  6. Camisa C, Bikowski JB, McDonald SG. Cowden’s disease. Association with squamous cell carcinoma of the tongue and perianal basal cell carcinoma. Arch Dermatol. 1984;120:677–678. doi: 10.1001/archderm.120.5.677. [DOI] [PubMed] [Google Scholar]
  7. Endersby R, Baker SJ. PTEN signaling in brain: neuropathology and tumorigenesis. Oncogene. 2008;27:5416–5430. doi: 10.1038/onc.2008.239. [DOI] [PubMed] [Google Scholar]
  8. Erb P, Ji J, Kump E, Mielgo A, Wernli M. Apoptosis and pathogenesis of melanoma and nonmelanoma skin cancer. Adv Exp Med Biol. 2008;624:283–295. doi: 10.1007/978-0-387-77574-6_22. [DOI] [PubMed] [Google Scholar]
  9. Gimm O, Perren A, Weng LP, Marsh DJ, Yeh JJ, Ziebold U, et al. Differential nuclear and cytoplasmic expression of PTEN in normal thyroid tissue, and benign and malignant epithelial thyroid tumors. Am J Pathol. 2000;156:1693–1700. doi: 10.1016/s0002-9440(10)65040-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Groszer M, Erickson R, Scripture-Adams DD, Lesche R, Trumpp A, Zack JA, et al. Negative regulation of neural stem/progenitor cell proliferation by the Pten tumor suppressor gene in vivo. Science. 2001;294:2186–2189. doi: 10.1126/science.1065518. [DOI] [PubMed] [Google Scholar]
  11. Harima Y, Sawada S, Nagata K, Sougawa M, Ostapenko V, Ohnishi T. Mutation of the PTEN gene in advanced cervical cancer correlated with tumor progression and poor outcome after radiotherapy. Int J Oncol. 2001;18:493–497. doi: 10.3892/ijo.18.3.493. [DOI] [PubMed] [Google Scholar]
  12. He XC, Yin T, Grindley JC, Tian Q, Sato T, Tao WA, et al. PTEN-deficient intestinal stem cells initiate intestinal polyposis. Nat Genet. 2007;39:189–198. doi: 10.1038/ng1928. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. He YY, Pi J, Huang JL, Diwan BA, Waalkes MP, Chignell CF. Chronic UVA irradiation of human HaCaT keratinocytes induces malignant transformation associated with acquired apoptotic resistance. Oncogene. 2006;25:3680–3688. doi: 10.1038/sj.onc.1209384. [DOI] [PubMed] [Google Scholar]
  14. Hocker T, Tsao H. Ultraviolet radiation and melanoma: a systematic review and analysis of reported sequence variants. Hum Mutat. 2007;28:578–588. doi: 10.1002/humu.20481. [DOI] [PubMed] [Google Scholar]
  15. Kimura T, Suzuki A, Fujita Y, Yomogida K, Lomeli H, Asada N, et al. Conditional loss of PTEN leads to testicular teratoma and enhances embryonic germ cell production. Development. 2003;130:1691–1700. doi: 10.1242/dev.00392. [DOI] [PubMed] [Google Scholar]
  16. Kohno T, Takahashi M, Manda R, Yokota J. Inactivation of the PTEN/MMAC1/TEP1 gene in human lung cancers. Genes Chromosomes Cancer. 1998;22:152–156. doi: 10.1002/(sici)1098-2264(199806)22:2<152::aid-gcc10>3.0.co;2-s. [DOI] [PubMed] [Google Scholar]
  17. Kubo Y, Urano Y, Hida Y, Arase S. Lack of somatic mutation in the PTEN gene in squamous cell carcinomas of human skin. J Dermatol Sci. 1999;19:199–201. doi: 10.1016/s0923-1811(98)00058-9. [DOI] [PubMed] [Google Scholar]
  18. Li G, Robinson GW, Lesche R, Martinez-Diaz H, Jiang Z, Rozengurt N, et al. Conditional loss of PTEN leads to precocious development and neoplasia in the mammary gland. Development. 2002;129:4159–4170. doi: 10.1242/dev.129.17.4159. [DOI] [PubMed] [Google Scholar]
  19. Liaw D, Marsh DJ, Li J, Dahia PL, Wang SI, Zheng Z, et al. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet. 1997;16:64–67. doi: 10.1038/ng0597-64. [DOI] [PubMed] [Google Scholar]
  20. Maehama T, Dixon JE. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem. 1998;273:13375–13378. doi: 10.1074/jbc.273.22.13375. [DOI] [PubMed] [Google Scholar]
  21. Marsh DJ, Dahia PL, Zheng Z, Liaw D, Parsons R, Gorlin RJ, et al. Germline mutations in PTEN are present in Bannayan-Zonana syndrome. Nat Genet. 1997;16:333–334. doi: 10.1038/ng0897-333. [DOI] [PubMed] [Google Scholar]
  22. Murao K, Kubo Y, Ohtani N, Hara E, Arase S. Epigenetic abnormalities in cutaneous squamous cell carcinomas: frequent inactivation of the RB1/p16 and p53 pathways. Br J Dermatol. 2006;155:999–1005. doi: 10.1111/j.1365-2133.2006.07487.x. [DOI] [PubMed] [Google Scholar]
  23. Nuss DD, Aeling JL, Clemons DE, Weber WN. Multiple hamartoma syndrome (Cowden’s disease) Arch Dermatol. 1978;114:743–746. [PubMed] [Google Scholar]
  24. Oh JH, Kim A, Park JM, Kim SH, Chung AS. Ultraviolet B-induced matrix metalloproteinase-1 and -3 secretions are mediated via PTEN/Akt pathway in human dermal fibroblasts. J Cell Physiol. 2006;209:775–785. doi: 10.1002/jcp.20754. [DOI] [PubMed] [Google Scholar]
  25. Quinn AG, Sikkink S, Rees JL. Basal cell carcinomas and squamous cell carcinomas of human skin show distinct patterns of chromosome loss. Cancer Res. 1994;54:4756–4759. [PubMed] [Google Scholar]
  26. Ramos J, Villa J, Ruiz A, Armstrong R, Matta J. UV dose determines key characteristics of nonmelanoma skin cancer. Cancer Epidemiol Biomarkers Prev. 2004;13:2006–2011. [PubMed] [Google Scholar]
  27. Reifenberger J. [Basal cell carcinoma. Molecular genetics and unusual clinical features] Hautarzt. 2007;58:406–411. doi: 10.1007/s00105-007-1324-y. [DOI] [PubMed] [Google Scholar]
  28. Rigel DS. Cutaneous ultraviolet exposure and its relationship to the development of skin cancer. J Am Acad Dermatol. 2008;58:S129–S132. doi: 10.1016/j.jaad.2007.04.034. [DOI] [PubMed] [Google Scholar]
  29. Riobo NA, Lu K, Ai X, Haines GM, Emerson CP., Jr Phosphoinositide 3-kinase and Akt are essential for Sonic Hedgehog signaling. Proc Natl Acad Sci USA. 2006;103:4505–4510. doi: 10.1073/pnas.0504337103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Robertson GP. Functional and therapeutic significance of Akt deregulation in malignant melanoma. Cancer Metastasis Rev. 2005;24:273–285. doi: 10.1007/s10555-005-1577-9. [DOI] [PubMed] [Google Scholar]
  31. Segrelles C, Ruiz S, Perez P, Murga C, Santos M, Budunova IV, et al. Functional roles of Akt signaling in mouse skin tumorigenesis. Oncogene. 2002;21:53–64. doi: 10.1038/sj.onc.1205032. [DOI] [PubMed] [Google Scholar]
  32. Shen WH, Balajee AS, Wang J, Wu H, Eng C, Pandolfi PP, et al. Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell. 2007;128:157–170. doi: 10.1016/j.cell.2006.11.042. [DOI] [PubMed] [Google Scholar]
  33. Stahl JM, Sharma A, Cheung M, Zimmerman M, Cheng JQ, Bosenberg MW, et al. Deregulated Akt3 activity promotes development of malignant melanoma. Cancer Res. 2004;64:7002–7010. doi: 10.1158/0008-5472.CAN-04-1399. [DOI] [PubMed] [Google Scholar]
  34. Stambolic V, Suzuki A, de la Pompa JL, Brothers GM, Mirtsos C, Sasaki T, et al. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell. 1998;95:29–39. doi: 10.1016/s0092-8674(00)81780-8. [DOI] [PubMed] [Google Scholar]
  35. Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet. 1997;15:356–362. doi: 10.1038/ng0497-356. [DOI] [PubMed] [Google Scholar]
  36. Suzuki A, de la Pompa JL, Stambolic V, Elia AJ, Sasaki T, del Barco Barrantes I, et al. High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. Curr Biol. 1998;8:1169–1178. doi: 10.1016/s0960-9822(07)00488-5. [DOI] [PubMed] [Google Scholar]
  37. Suzuki A, Itami S, Ohishi M, Hamada K, Inoue T, Komazawa N, et al. Keratinocyte-specific Pten deficiency results in epidermal hyperplasia, accelerated hair follicle morphogenesis and tumor formation. Cancer Res. 2003;63:674–681. [PubMed] [Google Scholar]
  38. Suzuki A, Nakano T, Mak TW, Sasaki T. Portrait of PTEN: messages from mutant mice. Cancer Sci. 2008;99:209–213. doi: 10.1111/j.1349-7006.2007.00670.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Trojan J, Plotz G, Brieger A, Raedle J, Meltzer SJ, Wolter M, et al. Activation of a cryptic splice site of PTEN and loss of heterozygosity in benign skin lesions in Cowden disease. J Invest Dermatol. 2001;117:1650–1653. doi: 10.1046/j.0022-202x.2001.01954.x. [DOI] [PubMed] [Google Scholar]
  40. Tsao H, Goel V, Wu H, Yang G, Haluska FG. Genetic interaction between NRAS and BRAF mutations and PTEN/MMAC1 inactivation in melanoma. J Invest Dermatol. 2004;122:337–341. doi: 10.1046/j.0022-202X.2004.22243.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Tsao H, Zhang X, Benoit E, Haluska FG. Identification of PTEN/MMAC1 alterations in uncultured melanomas and melanoma cell lines. Oncogene. 1998;16:3397–3402. doi: 10.1038/sj.onc.1201881. [DOI] [PubMed] [Google Scholar]
  42. Virolle T, Adamson ED, Baron V, Birle D, Mercola D, Mustelin T, et al. The Egr-1 transcription factor directly activates PTEN during irradiation-induced signalling. Nat Cell Biol. 2001;3:1124–1128. doi: 10.1038/ncb1201-1124. [DOI] [PubMed] [Google Scholar]
  43. Wang S, Garcia AJ, Wu M, Lawson DA, Witte ON, Wu H. Pten deletion leads to the expansion of a prostatic stem/progenitor cell subpopulation and tumor initiation. Proc Natl Acad Sci USA. 2006;103:1480–1485. doi: 10.1073/pnas.0510652103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Wu H, Goel V, Haluska FG. PTEN signaling pathways in melanoma. Oncogene. 2003;22:3113–3122. doi: 10.1038/sj.onc.1206451. [DOI] [PubMed] [Google Scholar]
  45. Yanagi S, Kishimoto H, Kawahara K, Sasaki T, Sasaki M, Nishio M, et al. Pten controls lung morphogenesis, bronchioalveolar stem cells, and onset of lung adenocarcinomas in mice. J Clin Invest. 2007;117:2929–2940. doi: 10.1172/JCI31854. [DOI] [PMC free article] [PubMed] [Google Scholar]

RESOURCES