Skip to main content
NCBI home page
Molecular Medicine logoLink to Molecular Medicine
. 1998 Dec;4(12):807–822.

Alterations of p16-pRb pathway and chromosome locus 9p21-22 in sporadic invasive breast carcinomas.

V G Gorgoulis 1, E N Koutroumbi 1, A Kotsinas 1, P Zacharatos 1, C Markopoulos 1, L Giannikos 1, V Kyriakou 1, Z Voulgaris 1, I Gogas 1, C Kittas 1
PMCID: PMC2230392  PMID: 9990866

Abstract

The p16-pRb pathway represents a vital cell-cycle checkpoint. In the present study we investigated the alterations of this G1-phase protein pathway using immunohistochemical and molecular methods in a series of 55 breast carcinomas and correlated the findings with clinicopathological features of the patients. Furthermore, we examined its relationship with the status of the chromosomal region 9p21-22 performing a deletion map analysis because there are indications that, in addition to CDKN2 and MTS2/p15(INK4B) tumor suppressor genes (TSGs), this area harbors other TSG(s). Aberrant expression (Ab) of p16 and pRb was observed in 26 (47%) and 16 (29%) of the carcinomas, respectively. A statistical trend pointing out an inverse relationship between p16 and pRb expression was found (p = 0.079). Analysis of the region that encodes for p16 by deletion mapping, a PCR-based methylation assay and PCR-SSCP, revealed that deletions and transcriptional silencing by methylation might represent the main mechanisms of CDKN2/p16(INK4A) inactivation in breast carcinomas. The results of deletion mapping also suggest that another TSG(s) may reside at the 9p21-22 area particularly at the D9S162 loci and that co-deletion of this putative gene with CDKN2/p16(INK4A) may play a role in breast carcinogenesis. In addition, microsatellite instability (MI), a marker of replication error phenotype (RER+), was observed with a frequency of 16% in the area examined and was inversely related with loss of heterozygosity (LOH). Interestingly, most cases with MI at the region encoding for p16 were aggregated in a subgroup of breast carcinomas with no other obvious genetic and/or epigenetic CDKN2/p16(INK4A) alterations. We speculate that there is an additional mechanism of CDKN2/p16(INK4A) inactivation. The relationship of p16 protein level pRb, status, the p16-pRb combined immunoprofiles, and the microsatellite alterations detected at the 9p21-22 locus with the patients' clinicopathological parameters revealed two significant correlations: one between normal pRb expression and lymph node involvement (p = 0.0263), and the other between microsatellite alterations (LOH and or MI) and tumor size (p = 9.2 x 10(-3)). In view of the heterogenous nature of breast cancer, we suggest that in a significant proportion of breast carcinomas, deregulation of the p16-pRb pathway in association with another, as-yet unidentified, TSG(s) of the 9p21-22 region may play a role in initiating or progressing the oncogenic procedure, while in other subgroups, alternative molecules may play this role.

Full text

PDF
807

Images in this article

812Fig. 1
on p.812
813Fig. 2
on p.813
813Fig. 3
on p.813
814Fig. 4
on p.814
816Fig. 5
on p.816

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Albigès-Rizo C., Frachet P., Block M. R. Down regulation of talin alters cell adhesion and the processing of the alpha 5 beta 1 integrin. J Cell Sci. 1995 Oct;108(Pt 10):3317–3329. doi: 10.1242/jcs.108.10.3317. [DOI] [PubMed] [Google Scholar]
  2. Anderson J. J., Tiniakos D. G., McIntosh G. G., Autzen P., Henry J. A., Thomas M. D., Reed J., Horne G. M., Lennard T. W., Angus B. Retinoblastoma protein in human breast carcinoma: immunohistochemical study using a new monoclonal antibody effective on routinely processed tissues. J Pathol. 1996 Sep;180(1):65–70. doi: 10.1002/(SICI)1096-9896(199609)180:1<65::AID-PATH607>3.0.CO;2-C. [DOI] [PubMed] [Google Scholar]
  3. BLOOM H. J., RICHARDSON W. W. Histological grading and prognosis in breast cancer; a study of 1409 cases of which 359 have been followed for 15 years. Br J Cancer. 1957 Sep;11(3):359–377. doi: 10.1038/bjc.1957.43. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Barbareschi M., Pelosio P., Caffo O., Buttitta F., Pellegrini S., Barbazza R., Dalla Palma P., Bevilacqua G., Marchetti A. Cyclin-D1-gene amplification and expression in breast carcinoma: relation with clinicopathologic characteristics and with retinoblastoma gene product, p53 and p21WAF1 immunohistochemical expression. Int J Cancer. 1997 Apr 22;74(2):171–174. doi: 10.1002/(sici)1097-0215(19970422)74:2<171::aid-ijc5>3.0.co;2-w. [DOI] [PubMed] [Google Scholar]
  5. Berns E. M., Klijn J. G., Smid M., van Staveren I. L., Gruis N. A., Foekens J. A. Infrequent CDKN2 (MTS1/p16) gene alterations in human primary breast cancer. Br J Cancer. 1995 Oct;72(4):964–967. doi: 10.1038/bjc.1995.442. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Berns E. M., de Klein A., van Putten W. L., van Staveren I. L., Bootsma A., Klijn J. G., Foekens J. A. Association between RB-1 gene alterations and factors of favourable prognosis in human breast cancer, without effect on survival. Int J Cancer. 1995 Apr 21;64(2):140–145. doi: 10.1002/ijc.2910640212. [DOI] [PubMed] [Google Scholar]
  7. Borg A., Zhang Q. X., Alm P., Olsson H., Sellberg G. The retinoblastoma gene in breast cancer: allele loss is not correlated with loss of gene protein expression. Cancer Res. 1992 May 15;52(10):2991–2994. [PubMed] [Google Scholar]
  8. Brenner A. J., Aldaz C. M. Chromosome 9p allelic loss and p16/CDKN2 in breast cancer and evidence of p16 inactivation in immortal breast epithelial cells. Cancer Res. 1995 Jul 1;55(13):2892–2895. [PubMed] [Google Scholar]
  9. Cairns P., Mao L., Merlo A., Lee D. J., Schwab D., Eby Y., Tokino K., van der Riet P., Blaugrund J. E., Sidransky D. Rates of p16 (MTS1) mutations in primary tumors with 9p loss. Science. 1994 Jul 15;265(5170):415–417. doi: 10.1126/science.8023167. [DOI] [PubMed] [Google Scholar]
  10. Chaubert P., Guillou L., Kurt A. M., Bertholet M. M., Metthez G., Leisinger H. J., Bosman F., Shaw P. Frequent p16INK4 (MTS1) gene inactivation in testicular germ cell tumors. Am J Pathol. 1997 Sep;151(3):859–865. [PMC free article] [PubMed] [Google Scholar]
  11. Cordon-Cardo C. Mutations of cell cycle regulators. Biological and clinical implications for human neoplasia. Am J Pathol. 1995 Sep;147(3):545–560. [PMC free article] [PubMed] [Google Scholar]
  12. Devilee P., Cornelisse C. J. Somatic genetic changes in human breast cancer. Biochim Biophys Acta. 1994 Dec 30;1198(2-3):113–130. doi: 10.1016/0304-419x(94)90009-4. [DOI] [PubMed] [Google Scholar]
  13. Dublin E. A., Patel N. K., Gillett C. E., Smith P., Peters G., Barnes D. M. Retinoblastoma and p16 proteins in mammary carcinoma: their relationship to cyclin D1 and histopathological parameters. Int J Cancer. 1998 Feb 20;79(1):71–75. doi: 10.1002/(sici)1097-0215(19980220)79:1<71::aid-ijc14>3.0.co;2-k. [DOI] [PubMed] [Google Scholar]
  14. Fong K. M., Zimmerman P. V., Smith P. J. Microsatellite instability and other molecular abnormalities in non-small cell lung cancer. Cancer Res. 1995 Jan 1;55(1):28–30. [PubMed] [Google Scholar]
  15. Geradts J., Hu S. X., Lincoln C. E., Benedict W. F., Xu H. J. Aberrant RB gene expression in routinely processed, archival tumor tissues determined by three different anti-RB antibodies. Int J Cancer. 1994 Jul 15;58(2):161–167. doi: 10.1002/ijc.2910580203. [DOI] [PubMed] [Google Scholar]
  16. Geradts J., Wilson P. A. High frequency of aberrant p16(INK4A) expression in human breast cancer. Am J Pathol. 1996 Jul;149(1):15–20. [PMC free article] [PubMed] [Google Scholar]
  17. Gilmore A. P., Ohanian V., Spurr N. K., Critchley D. R. Localisation of the human gene encoding the cytoskeletal protein talin to chromosome 9p. Hum Genet. 1995 Aug;96(2):221–224. doi: 10.1007/BF00207384. [DOI] [PubMed] [Google Scholar]
  18. Glebov O. K., McKenzie K. E., White C. A., Sukumar S. Frequent p53 gene mutations and novel alleles in familial breast cancer. Cancer Res. 1994 Jul 15;54(14):3703–3709. [PubMed] [Google Scholar]
  19. Gonzalez-Zulueta M., Bender C. M., Yang A. S., Nguyen T., Beart R. W., Van Tornout J. M., Jones P. A. Methylation of the 5' CpG island of the p16/CDKN2 tumor suppressor gene in normal and transformed human tissues correlates with gene silencing. Cancer Res. 1995 Oct 15;55(20):4531–4535. [PubMed] [Google Scholar]
  20. Gorgoulis V. G., Rassidakis G. Z., Karameris A. M., Papastamatiou H., Trigidou R., Veslemes M., Rassidakis A. N., Kittas C. Immunohistochemical and molecular evaluation of the mdm-2 gene product in bronchogenic carcinoma. Mod Pathol. 1996 May;9(5):544–554. [PubMed] [Google Scholar]
  21. Gorgoulis V. G., Zacharatos P., Kotsinas A., Liloglou T., Kyroudi A., Veslemes M., Rassidakis A., Halazonetis T. D., Field J. K., Kittas C. Alterations of the p16-pRb pathway and the chromosome locus 9p21-22 in non-small-cell lung carcinomas: relationship with p53 and MDM2 protein expression. Am J Pathol. 1998 Dec;153(6):1749–1765. doi: 10.1016/S0002-9440(10)65690-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Gorgoulis V. G., Zoumpourlis V., Rassidakis G. Z., Karameris A., Rassidakis A. N., Spandidos D. A., Kittas C. A molecular and immunohistochemical study of the MDM2 protein isoforms and p53 gene product in bronchogenic carcinoma. J Pathol. 1996 Oct;180(2):129–137. doi: 10.1002/(SICI)1096-9896(199610)180:2<129::AID-PATH646>3.0.CO;2-8. [DOI] [PubMed] [Google Scholar]
  23. Gorgoulis V., Zoumpourlis V., Rassidakis G., Karameris A., Barbatis C., Spandidos D. A., Kittas C. Molecular analysis of p53 gene in laryngeal premalignant and malignant lesions. p53 protein immunohistochemical expression is positively related to proliferating cell nuclear antigen labelling index. Virchows Arch. 1995;426(4):339–344. doi: 10.1007/BF00191341. [DOI] [PubMed] [Google Scholar]
  24. Hangaishi A., Ogawa S., Imamura N., Miyawaki S., Miura Y., Uike N., Shimazaki C., Emi N., Takeyama K., Hirosawa S. Inactivation of multiple tumor-suppressor genes involved in negative regulation of the cell cycle, MTS1/p16INK4A/CDKN2, MTS2/p15INK4B, p53, and Rb genes in primary lymphoid malignancies. Blood. 1996 Jun 15;87(12):4949–4958. [PubMed] [Google Scholar]
  25. Herman J. G., Merlo A., Mao L., Lapidus R. G., Issa J. P., Davidson N. E., Sidransky D., Baylin S. B. Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers. Cancer Res. 1995 Oct 15;55(20):4525–4530. [PubMed] [Google Scholar]
  26. Ito Y., Kobayashi T., Takeda T., Nakano Y., Tamaki Y., Komoike Y., Wakasugi E., Shin E., Takatsuka Y., Kikkawa N. Expression of p16 and cyclin-dependent kinase 4 proteins in primary breast carcinomas. Oncology. 1997 Nov-Dec;54(6):508–515. doi: 10.1159/000227611. [DOI] [PubMed] [Google Scholar]
  27. Jares P., Rey M. J., Fernández P. L., Campo E., Nadal A., Muñoz M., Mallofré C., Muntané J., Nayach I., Estapé J. Cyclin D1 and retinoblastoma gene expression in human breast carcinoma: correlation with tumour proliferation and oestrogen receptor status. J Pathol. 1997 Jun;182(2):160–166. doi: 10.1002/(SICI)1096-9896(199706)182:2<160::AID-PATH814>3.0.CO;2-2. [DOI] [PubMed] [Google Scholar]
  28. Jiricny J. Colon cancer and DNA repair: have mismatches met their match? Trends Genet. 1994 May;10(5):164–168. doi: 10.1016/0168-9525(94)90093-0. [DOI] [PubMed] [Google Scholar]
  29. Kamb A., Gruis N. A., Weaver-Feldhaus J., Liu Q., Harshman K., Tavtigian S. V., Stockert E., Day R. S., 3rd, Johnson B. E., Skolnick M. H. A cell cycle regulator potentially involved in genesis of many tumor types. Science. 1994 Apr 15;264(5157):436–440. doi: 10.1126/science.8153634. [DOI] [PubMed] [Google Scholar]
  30. Kinne D. W. Staging and follow-up of breast cancer patients. Cancer. 1991 Feb 15;67(4 Suppl):1196–1198. doi: 10.1002/1097-0142(19910215)67:4+<1196::aid-cncr2820671515>3.0.co;2-4. [DOI] [PubMed] [Google Scholar]
  31. Kinoshita I., Dosaka-Akita H., Mishina T., Akie K., Nishi M., Hiroumi H., Hommura F., Kawakami Y. Altered p16INK4 and retinoblastoma protein status in non-small cell lung cancer: potential synergistic effect with altered p53 protein on proliferative activity. Cancer Res. 1996 Dec 15;56(24):5557–5562. [PubMed] [Google Scholar]
  32. Knudson A. G. Antioncogenes and human cancer. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):10914–10921. doi: 10.1073/pnas.90.23.10914. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Koh J., Enders G. H., Dynlacht B. D., Harlow E. Tumour-derived p16 alleles encoding proteins defective in cell-cycle inhibition. Nature. 1995 Jun 8;375(6531):506–510. doi: 10.1038/375506a0. [DOI] [PubMed] [Google Scholar]
  34. Li Y., Nichols M. A., Shay J. W., Xiong Y. Transcriptional repression of the D-type cyclin-dependent kinase inhibitor p16 by the retinoblastoma susceptibility gene product pRb. Cancer Res. 1994 Dec 1;54(23):6078–6082. [PubMed] [Google Scholar]
  35. Markowitz S., Wang J., Myeroff L., Parsons R., Sun L., Lutterbaugh J., Fan R. S., Zborowska E., Kinzler K. W., Vogelstein B. Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science. 1995 Jun 2;268(5215):1336–1338. doi: 10.1126/science.7761852. [DOI] [PubMed] [Google Scholar]
  36. Marsh K. L., Varley J. M. Frequent alterations of cell cycle regulators in early-stage breast lesions as detected by immunohistochemistry. Br J Cancer. 1998 May;77(9):1460–1468. doi: 10.1038/bjc.1998.240. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Marsh K. L., Varley J. M. Loss of heterozygosity at chromosome 9p in ductal carcinoma in situ and invasive carcinoma of the breast. Br J Cancer. 1998 May;77(9):1439–1447. doi: 10.1038/bjc.1998.237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Medema R. H., Herrera R. E., Lam F., Weinberg R. A. Growth suppression by p16ink4 requires functional retinoblastoma protein. Proc Natl Acad Sci U S A. 1995 Jul 3;92(14):6289–6293. doi: 10.1073/pnas.92.14.6289. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Merlo A., Herman J. G., Mao L., Lee D. J., Gabrielson E., Burger P. C., Baylin S. B., Sidransky D. 5' CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nat Med. 1995 Jul;1(7):686–692. doi: 10.1038/nm0795-686. [DOI] [PubMed] [Google Scholar]
  40. Merlo A., Mabry M., Gabrielson E., Vollmer R., Baylin S. B., Sidransky D. Frequent microsatellite instability in primary small cell lung cancer. Cancer Res. 1994 Apr 15;54(8):2098–2101. [PubMed] [Google Scholar]
  41. Merlo A., Mabry M., Gabrielson E., Vollmer R., Baylin S. B., Sidransky D. Frequent microsatellite instability in primary small cell lung cancer. Cancer Res. 1994 Apr 15;54(8):2098–2101. [PubMed] [Google Scholar]
  42. Mouridsen H. T., Palshof T., Mattheiem W., Sylvester R. J., Rotmensz N., Paridaens R. J. Currently active protocols in the EORTC Breast Cancer Cooperative Group. Recent Results Cancer Res. 1984;91:263–267. doi: 10.1007/978-3-642-82188-2_38. [DOI] [PubMed] [Google Scholar]
  43. Musgrove E. A., Lilischkis R., Cornish A. L., Lee C. S., Setlur V., Seshadri R., Sutherland R. L. Expression of the cyclin-dependent kinase inhibitors p16INK4, p15INK4B and p21WAF1/CIP1 in human breast cancer. Int J Cancer. 1995 Nov 15;63(4):584–591. doi: 10.1002/ijc.2910630420. [DOI] [PubMed] [Google Scholar]
  44. Neville E. M., Stewart M., Myskow M., Donnelly R. J., Field J. K. Loss of heterozygosity at 9p23 defines a novel locus in non-small cell lung cancer. Oncogene. 1995 Aug 3;11(3):581–585. [PubMed] [Google Scholar]
  45. Nielsen N. H., Emdin S. O., Cajander J., Landberg G. Deregulation of cyclin E and D1 in breast cancer is associated with inactivation of the retinoblastoma protein. Oncogene. 1997 Jan 23;14(3):295–304. doi: 10.1038/sj.onc.1200833. [DOI] [PubMed] [Google Scholar]
  46. Nobori T., Miura K., Wu D. J., Lois A., Takabayashi K., Carson D. A. Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers. Nature. 1994 Apr 21;368(6473):753–756. doi: 10.1038/368753a0. [DOI] [PubMed] [Google Scholar]
  47. Okamoto A., Demetrick D. J., Spillare E. A., Hagiwara K., Hussain S. P., Bennett W. P., Forrester K., Gerwin B., Serrano M., Beach D. H. Mutations and altered expression of p16INK4 in human cancer. Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):11045–11049. doi: 10.1073/pnas.91.23.11045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Olopade O. I., Pomykala H. M., Hagos F., Sveen L. W., Espinosa R., 3rd, Dreyling M. H., Gursky S., Stadler W. M., Le Beau M. M., Bohlander S. K. Construction of a 2.8-megabase yeast artificial chromosome contig and cloning of the human methylthioadenosine phosphorylase gene from the tumor suppressor region on 9p21. Proc Natl Acad Sci U S A. 1995 Jul 3;92(14):6489–6493. doi: 10.1073/pnas.92.14.6489. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Otterson G. A., Khleif S. N., Chen W., Coxon A. B., Kaye F. J. CDKN2 gene silencing in lung cancer by DNA hypermethylation and kinetics of p16INK4 protein induction by 5-aza 2'deoxycytidine. Oncogene. 1995 Sep 21;11(6):1211–1216. [PubMed] [Google Scholar]
  50. Patel U., Grundfest-Broniatowski S., Gupta M., Banerjee S. Microsatellite instabilities at five chromosomes in primary breast tumors. Oncogene. 1994 Dec;9(12):3695–3700. [PubMed] [Google Scholar]
  51. Paulson T. G., Wright F. A., Parker B. A., Russack V., Wahl G. M. Microsatellite instability correlates with reduced survival and poor disease prognosis in breast cancer. Cancer Res. 1996 Sep 1;56(17):4021–4026. [PubMed] [Google Scholar]
  52. Quesnel B., Fenaux P., Philippe N., Fournier J., Bonneterre J., Preudhomme C., Peyrat J. P. Analysis of p16 gene deletion and point mutation in breast carcinoma. Br J Cancer. 1995 Aug;72(2):351–353. doi: 10.1038/bjc.1995.337. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Reissmann P. T., Koga H., Takahashi R., Figlin R. A., Holmes E. C., Piantadosi S., Cordon-Cardo C., Slamon D. J. Inactivation of the retinoblastoma susceptibility gene in non-small-cell lung cancer. The Lung Cancer Study Group. Oncogene. 1993 Jul;8(7):1913–1919. [PubMed] [Google Scholar]
  54. Rush E. B., Abouezzi Z., Borgen P. I., Anelli A. Analysis of MTS1/CDK4 in female breast carcinomas. Cancer Lett. 1995 Mar 2;89(2):223–226. doi: 10.1016/0304-3835(95)03691-o. [DOI] [PubMed] [Google Scholar]
  55. Sakaguchi M., Fujii Y., Hirabayashi H., Yoon H. E., Komoto Y., Oue T., Kusafuka T., Okada A., Matsuda H. Inversely correlated expression of p16 and Rb protein in non-small cell lung cancers: an immunohistochemical study. Int J Cancer. 1996 Feb 8;65(4):442–445. doi: 10.1002/(SICI)1097-0215(19960208)65:4<442::AID-IJC8>3.0.CO;2-X. [DOI] [PubMed] [Google Scholar]
  56. Sawan A., Randall B., Angus B., Wright C., Henry J. A., Ostrowski J., Hennessy C., Lennard T. W., Corbett I., Horne C. H. Retinoblastoma and p53 gene expression related to relapse and survival in human breast cancer: an immunohistochemical study. J Pathol. 1992 Sep;168(1):23–28. doi: 10.1002/path.1711680105. [DOI] [PubMed] [Google Scholar]
  57. Serrano M., Hannon G. J., Beach D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature. 1993 Dec 16;366(6456):704–707. doi: 10.1038/366704a0. [DOI] [PubMed] [Google Scholar]
  58. Shaw J. A., Walsh T., Chappell S. A., Carey N., Johnson K., Walker R. A. Microsatellite instability in early sporadic breast cancer. Br J Cancer. 1996 Jun;73(11):1393–1397. doi: 10.1038/bjc.1996.264. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Spruck C. H., 3rd, Gonzalez-Zulueta M., Shibata A., Simoneau A. R., Lin M. F., Gonzales F., Tsai Y. C., Jones P. A. p16 gene in uncultured tumours. Nature. 1994 Jul 21;370(6486):183–184. doi: 10.1038/370183a0. [DOI] [PubMed] [Google Scholar]
  60. T'Ang A., Varley J. M., Chakraborty S., Murphree A. L., Fung Y. K. Structural rearrangement of the retinoblastoma gene in human breast carcinoma. Science. 1988 Oct 14;242(4876):263–266. doi: 10.1126/science.3175651. [DOI] [PubMed] [Google Scholar]
  61. Tam S. W., Shay J. W., Pagano M. Differential expression and cell cycle regulation of the cyclin-dependent kinase 4 inhibitor p16Ink4. Cancer Res. 1994 Nov 15;54(22):5816–5820. [PubMed] [Google Scholar]
  62. Thibodeau S. N., Bren G., Schaid D. Microsatellite instability in cancer of the proximal colon. Science. 1993 May 7;260(5109):816–819. doi: 10.1126/science.8484122. [DOI] [PubMed] [Google Scholar]
  63. Thorlacius S., Jonasdottir O., Eyfjord J. E. Loss of heterozygosity at selective sites on chromosomes 13 and 17 in human breast carcinoma. Anticancer Res. 1991 Jul-Aug;11(4):1501–1507. [PubMed] [Google Scholar]
  64. Trudel M., Mulligan L., Cavenee W., Margolese R., Côté J., Gariépy G. Retinoblastoma and p53 gene product expression in breast carcinoma: immunohistochemical analysis and clinicopathologic correlation. Hum Pathol. 1992 Dec;23(12):1388–1394. doi: 10.1016/0046-8177(92)90059-c. [DOI] [PubMed] [Google Scholar]
  65. Ueki K., Ono Y., Henson J. W., Efird J. T., von Deimling A., Louis D. N. CDKN2/p16 or RB alterations occur in the majority of glioblastomas and are inversely correlated. Cancer Res. 1996 Jan 1;56(1):150–153. [PubMed] [Google Scholar]
  66. Van Zee K. J., Calvano J. E., Bisogna M. Hypomethylation and increased gene expression of p16INK4a in primary and metastatic breast carcinoma as compared to normal breast tissue. Oncogene. 1998 May 28;16(21):2723–2727. doi: 10.1038/sj.onc.1201794. [DOI] [PubMed] [Google Scholar]
  67. Varley J. M., Armour J., Swallow J. E., Jeffreys A. J., Ponder B. A., T'Ang A., Fung Y. K., Brammar W. J., Walker R. A. The retinoblastoma gene is frequently altered leading to loss of expression in primary breast tumours. Oncogene. 1989 Jun;4(6):725–729. [PubMed] [Google Scholar]
  68. Wang Y., Becker D. Differential expression of the cyclin-dependent kinase inhibitors p16 and p21 in the human melanocytic system. Oncogene. 1996 Mar 7;12(5):1069–1075. [PubMed] [Google Scholar]
  69. Wooster R., Cleton-Jansen A. M., Collins N., Mangion J., Cornelis R. S., Cooper C. S., Gusterson B. A., Ponder B. A., von Deimling A., Wiestler O. D. Instability of short tandem repeats (microsatellites) in human cancers. Nat Genet. 1994 Feb;6(2):152–156. doi: 10.1038/ng0294-152. [DOI] [PubMed] [Google Scholar]
  70. Xu H. J., Hu S. X., Benedict W. F. Lack of nuclear RB protein staining in G0/middle G1 cells: correlation to changes in total RB protein level. Oncogene. 1991 Jul;6(7):1139–1146. [PubMed] [Google Scholar]
  71. Xu L., Sgroi D., Sterner C. J., Beauchamp R. L., Pinney D. M., Keel S., Ueki K., Rutter J. L., Buckler A. J., Louis D. N. Mutational analysis of CDKN2 (MTS1/p16ink4) in human breast carcinomas. Cancer Res. 1994 Oct 15;54(20):5262–5264. [PubMed] [Google Scholar]
  72. Yeager T., Stadler W., Belair C., Puthenveettil J., Olopade O., Reznikoff C. Increased p16 levels correlate with pRb alterations in human urothelial cells. Cancer Res. 1995 Feb 1;55(3):493–497. [PubMed] [Google Scholar]
  73. Yee C. J., Roodi N., Verrier C. S., Parl F. F. Microsatellite instability and loss of heterozygosity in breast cancer. Cancer Res. 1994 Apr 1;54(7):1641–1644. [PubMed] [Google Scholar]
  74. Zhang S. Y., Klein-Szanto A. J., Sauter E. R., Shafarenko M., Mitsunaga S., Nobori T., Carson D. A., Ridge J. A., Goodrow T. L. Higher frequency of alterations in the p16/CDKN2 gene in squamous cell carcinoma cell lines than in primary tumors of the head and neck. Cancer Res. 1994 Oct 1;54(19):5050–5053. [PubMed] [Google Scholar]
  75. de Vos S., Miller C. W., Takeuchi S., Gombart A. F., Cho S. K., Koeffler H. P. Alterations of CDKN2 (p16) in non-small cell lung cancer. Genes Chromosomes Cancer. 1995 Nov;14(3):164–170. doi: 10.1002/gcc.2870140303. [DOI] [PubMed] [Google Scholar]

Articles from Molecular Medicine are provided here courtesy of The Feinstein Institute for Medical Research at North Shore LIJ

RESOURCES