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Gene Review

MKI67  -  marker of proliferation Ki-67

Homo sapiens

Synonyms: Antigen KI-67, KIA, MIB-, MIB-1, PPP1R105
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Disease relevance of MKI67


Psychiatry related information on MKI67

  • We conclude that the quantitative assessment of cytometric and morphometric features associated with proliferation and differentiation (especially Ki67 and SI) can be a valuable adjunct tool for clinical decision making in Barrett's oesophagus [6].
  • Recent studies, showing that cell cycle-related nuclear proteins p105 and Ki-67 are associated with Alzheimer's disease (AD)-related cytoskeletal pathology, suggested that these proteins, in addition to their functions in regulating the cell cycle, may have more specialised functions in the adult nervous system [7].
  • Neuronal nuclear expression of Ki-67 was increased in AD but was also elevated in young Down's syndrome subjects and in those with Pick's disease [7].
  • OBJECTIVE: To evaluate the expression of bcl-2, p-53, Ki-67, and apoptosis as evidenced by nuclear DNA fragmentation in cervical biopsies obtained from human immunodeficiency virus (HIV)-seropositive and HIV-seronegative women with a history of intravenous drug abuse [8].
  • T-cell proliferation was studied by ex vivo bromodeoxyuridine (BrdU) incorporation and intracellular Ki67 staining in HIV-infected patients treated with antiretroviral therapy (ART) with or without IL-2 [9].

High impact information on MKI67


Chemical compound and disease context of MKI67


Biological context of MKI67

  • Ki-67 proliferation indices were significantly elevated in p-AKT-overexpressing regions, whereas expression of the apoptosis marker cleaved caspase 3 was generally low and not significantly different between the regions [18].
  • A novel nucleolar protein, NIFK, interacts with the forkhead associated domain of Ki-67 antigen in mitosis [19].
  • Interval cancers are characterized by high levels of expression of TFF1 and/or Ki67 suggesting that cell migration and cell division play important roles in the rapid progression of interval cancers [20].
  • The major statistical end point of the study was pre- versus posttreatment change in cell proliferation, as measured by changes in Ki67 labeling indices [21].
  • In contrast, Ki67, ploidy, SPF, and p53 failed to predict for response [22].

Anatomical context of MKI67


Associations of MKI67 with chemical compounds

  • RESULTS: The treatment-induced reduction in geometric mean Ki67 was significantly greater with letrozole (87%) than tamoxifen (75%; analysis of covariance P = 0.0009) [27].
  • Twenty-three of 92 tumors (25%) on tamoxifen and 14 of 93 on letrozole (15%) showed a paradoxical increase in Ki67 with treatment, and the majority of these cases was HER1/2 negative [27].
  • Results showed a strong correlation between Ki67 and the thymidine labeling index (r = 0.868, P < or = 0.001) [28].
  • Immunofluorescence microscopy studies detecting BrdU labeled mitotic chromosomes, Ki67 domains, and p220(NPAT) containing Cajal bodies revealed that the durations of the S ( approximately 8 h), G2 ( approximately 4 h), and M phases ( approximately 1 h) are similar in ES and somatic cells [29].
  • Ki-67 staining in benign, borderline, malignant primary and metastatic ovarian tumors: correlation with steroid receptors, epidermal-growth-factor receptor and cathepsin D [4].

Physical interactions of MKI67

  • Double labeling with antibodies to either ER or PgR coupled with either [3H]thymidine histoautoradiography or with antibodies to the Ki67 proliferation antigen indicates that dividing cells are separate from those expressing the receptors (although they are often in close proximity) [30].
  • Structure of human Ki67 FHA domain and its binding to a phosphoprotein fragment from hNIFK reveal unique recognition sites and new views to the structural basis of FHA domain functions [31].
  • The Ki-67 protein interacts with members of the heterochromatin protein 1 (HP1) family: a potential role in the regulation of higher-order chromatin structure [32].
  • No correlation could be found between GAL-LI, the level of GAL binding and proliferative activity as determined by immunostaining with the cell proliferation marker Ki-67 [33].

Co-localisations of MKI67


Regulatory relationships of MKI67

  • In immunofluorescence co-expression studies, Ki67-positive cells were negative for p16(INK4A) and BMI1-expressing cells also stained negatively for Ki67 [35].
  • We conclude that PCNA/cyclin expression detected by MAb may define different cell subpopulations in different cell types relative to those incorporating BrdU or expressing the target antigen for Ki-67 [36].
  • In dysplastic lesions, p53- and Ki67-coexpressing cells tended to locate in the same layers and expand in the lower layers of epithelium with the progression of dysplasia. p21-expressing cells shifted to the upper layers of the epithelium with the progression of dysplasia [37].
  • The distribution of hTR-expressing cells was similar to that of Ki-67-positive cells [38].
  • Ki-67 was almost exclusively expressed in ERbeta-positive cells [39].

Other interactions of MKI67

  • Response was evaluated using proliferation markers (Ki-67, proliferating cell nuclear antigen) and apoptosis markers in tissue samples obtained by Tru-cut biopsy before treatment, and at surgery after treatment [40].
  • ER expression (P =.03), absence of c-erbB-2 (P =.03), and a decrease in Ki67 on day 10 or day 21 of the first cycle (P <.05) significantly predicted for subsequent GCR [41].
  • Increase in PgR and decrease in Ki67 on day 14 significantly predicted for response to tamoxifen (P < 0.03 and P < 0.04, respectively) [42].
  • DNMT3B overexpression was significantly related to Scarff, Bloom, and Richardson histopathological grade III (P = 0.002), ERalpha negativity (P = 0.0015), and strong MKI67 expression (P = 3 x 10(-6)) [43].
  • No relationship was observed between Ki-67 staining and the E-cadherin mutation status (p = 1.00) [44].

Analytical, diagnostic and therapeutic context of MKI67

  • Having assembled a cohort of benign proliferative breast lesions of known outcome, we studied the expression of estrogen receptor-alpha (ER-alpha) and Ki-67 using morphometric image analysis as well as dual-labeled immunofluorescence in HUT foci and in surrounding normal lobules of 25 patients that progressed to breast cancer and 19 controls [2].
  • RESULTS: Primary tumor size < or =5 mm and histological grade 1 were associated with 100 and 95% (95% confidence interval, 92-98%) 9-year distant disease-free survival, respectively, whereas strong erbB2 expression or the presence of >20% Ki-67-positive cells was associated with >20% risk [45].
  • In addition, the expression of hormone receptors p53, bcl-2, c-erbB-2, and Ki-67 was evaluated by immunohistochemistry, and the DNA ploidy was determined by image cytometry [46].
  • All 54 cases showed immunostaining for Ki-67 and PCNA, and valuable mitotic index, whereas only a fraction of tumors (25 of 54 cases) exhibited PgRP expression [26].
  • Median RFS was shorter for patients with positive Ki-67 staining (40 months) than for patients with negative staining (80 months) but did not reach statistical significance [47].


  1. p53 protein accumulation and response to adjuvant chemotherapy in premenopausal women with node-negative early breast cancer. Clahsen, P.C., van de Velde, C.J., Duval, C., Pallud, C., Mandard, A.M., Delobelle-Deroide, A., van den Broek, L., Sahmoud, T.M., van de Vijver, M.J. J. Clin. Oncol. (1998) [Pubmed]
  2. Breast cancer risk in usual ductal hyperplasia is defined by estrogen receptor-alpha and Ki-67 expression. Shaaban, A.M., Sloane, J.P., West, C.R., Foster, C.S. Am. J. Pathol. (2002) [Pubmed]
  3. P53 expression in breast cancer. Cattoretti, G., Rilke, F., Andreola, S., D'Amato, L., Delia, D. Int. J. Cancer (1988) [Pubmed]
  4. Ki-67 staining in benign, borderline, malignant primary and metastatic ovarian tumors: correlation with steroid receptors, epidermal-growth-factor receptor and cathepsin D. Henzen-Logmans, S.C., Fieret, E.J., Berns, E.M., van der Burg, M.E., Klijn, J.G., Foekens, J.A. Int. J. Cancer (1994) [Pubmed]
  5. Valosin-containing protein (p97) and Ki-67 expression is a useful marker in detecting malignant behavior of pancreatic endocrine neoplasms. Yamamoto, S., Tomita, Y., Nakamori, S., Hoshida, Y., Iizuka, N., Okami, J., Nagano, H., Dono, K., Umeshita, K., Sakon, M., Ishikawa, O., Ohigashi, H., Aozasa, K., Monden, M. Oncology (2004) [Pubmed]
  6. Clinical decision making in Barrett's oesophagus can be supported by computerized immunoquantitation and morphometry of features associated with proliferation and differentiation. Polkowski, W., Baak, J.P., van Lanschot, J.J., Meijer, G.A., Schuurmans, L.T., Ten Kate, F.J., Obertop, H., Offerhaus, G.J. J. Pathol. (1998) [Pubmed]
  7. Expression of cell division markers in the hippocampus in Alzheimer's disease and other neurodegenerative conditions. Nagy, Z., Esiri, M.M., Smith, A.D. Acta Neuropathol. (1997) [Pubmed]
  8. Apoptosis-related proteins and cervical intraepithelial neoplasia in human immunodeficiency virus-seropositive women. Spinillo, A., Zara, F., Zappatore, R., Cesari, S., Bergante, C., Morbini, P. Gynecol. Oncol. (2004) [Pubmed]
  9. IL-2-induced CD4+ T-cell expansion in HIV-infected patients is associated with long-term decreases in T-cell proliferation. Sereti, I., Anthony, K.B., Martinez-Wilson, H., Lempicki, R., Adelsberger, J., Metcalf, J.A., Hallahan, C.W., Follmann, D., Davey, R.T., Kovacs, J.A., Lane, H.C. Blood (2004) [Pubmed]
  10. Evidence that human cardiac myocytes divide after myocardial infarction. Beltrami, A.P., Urbanek, K., Kajstura, J., Yan, S.M., Finato, N., Bussani, R., Nadal-Ginard, B., Silvestri, F., Leri, A., Beltrami, C.A., Anversa, P. N. Engl. J. Med. (2001) [Pubmed]
  11. The clinical significance of epidermal growth factor receptor (EGF-R) in human breast cancer: a review on 5232 patients. Klijn, J.G., Berns, P.M., Schmitz, P.I., Foekens, J.A. Endocr. Rev. (1992) [Pubmed]
  12. Turnover of CD4+ and CD8+ T lymphocytes in HIV-1 infection as measured by Ki-67 antigen. Sachsenberg, N., Perelson, A.S., Yerly, S., Schockmel, G.A., Leduc, D., Hirschel, B., Perrin, L. J. Exp. Med. (1998) [Pubmed]
  13. Comparison of estrogen and progesterone receptor, Ki-67, and p53 immunoreactivity in uterine endometrioid carcinoma and endometrioid carcinoma with squamous, mucinous, secretory, and ciliated cell differentiation. Lax, S.F., Pizer, E.S., Ronnett, B.M., Kurman, R.J. Hum. Pathol. (1998) [Pubmed]
  14. A significance of immunohistochemical determination of steroid receptors, cell proliferation factor Ki-67 and protein p53 in endometrial carcinoma. Oreskovic, S., Babic, D., Kalafatic, D., Barisic, D., Beketic-Oreskovic, L. Gynecol. Oncol. (2004) [Pubmed]
  15. Estimation of tumor growth fractions in archival formalin-fixed, paraffin-embedded tissues using two anti-PCNA/Cyclin monoclonal antibodies. Factors affecting reactivity. Gelb, A.B., Kamel, O.W., LeBrun, D.P., Warnke, R.A. Am. J. Pathol. (1992) [Pubmed]
  16. Immunohistochemical detection of progesterone receptors and the correlation with Ki-67 labeling indices in paraffin-embedded sections of meningiomas. Nagashima, G., Aoyagi, M., Wakimoto, H., Tamaki, M., Ohno, K., Hirakawa, K. Neurosurgery (1995) [Pubmed]
  17. Effects of daily low dose mifepristone on endometrial maturation and proliferation. Cameron, S.T., Critchley, H.O., Thong, K.J., Buckley, C.H., Williams, A.R., Baird, D.T. Hum. Reprod. (1996) [Pubmed]
  18. AKT activation in human glioblastomas enhances proliferation via TSC2 and S6 kinase signaling. Riemenschneider, M.J., Betensky, R.A., Pasedag, S.M., Louis, D.N. Cancer Res. (2006) [Pubmed]
  19. A novel nucleolar protein, NIFK, interacts with the forkhead associated domain of Ki-67 antigen in mitosis. Takagi, M., Sueishi, M., Saiwaki, T., Kametaka, A., Yoneda, Y. J. Biol. Chem. (2001) [Pubmed]
  20. High expression of the trefoil protein TFF1 in interval breast cancers. Crosier, M., Scott, D., Wilson, R.G., Griffiths, C.D., May, F.E., Westley, B.R. Am. J. Pathol. (2001) [Pubmed]
  21. Phase II clinical trial of N-(4-Hydroxyphenyl)retinamide and tamoxifen administration before definitive surgery for breast neoplasia. Singletary, S.E., Atkinson, E.N., Hoque, A., Sneige, N., Sahin, A.A., Fritsche, H.A., Lotan, R., Lu, T., Hittelman, W.N., Bevers, T.B., Stelling, C.B., Lippman, S.M. Clin. Cancer Res. (2002) [Pubmed]
  22. Prediction of response to neoadjuvant chemoendocrine therapy in primary breast carcinomas. Makris, A., Powles, T.J., Dowsett, M., Osborne, C.K., Trott, P.A., Fernando, I.N., Ashley, S.E., Ormerod, M.G., Titley, J.C., Gregory, R.K., Allred, D.C. Clin. Cancer Res. (1997) [Pubmed]
  23. Effects of mifepristone on proliferation and apoptosis of human endometrium in new users of medroxyprogesterone acetate. Jain, J.K., Li, A., Yang, W., Minoo, P., Felix, J.C. Hum. Reprod. (2006) [Pubmed]
  24. Detection of mutations in the cDNA of the proliferation marker Ki-67 protein in four tumor cell lines. Bubán, T., Schmidt, M., Broll, R., Antal-Szalmás, P., Duchrow, M. Cancer Genet. Cytogenet. (2004) [Pubmed]
  25. Expression of the cyclin kinase inhibitor, p27kip1, in developing and mature human kidney. Combs, H.L., Shankland, S.J., Setzer, S.V., Hudkins, K.L., Alpers, C.E. Kidney Int. (1998) [Pubmed]
  26. Endocrine tumors of the pancreas: Ki-67 immunoreactivity on paraffin sections is an independent predictor for malignancy: a comparative study with proliferating-cell nuclear antigen and progesterone receptor protein immunostaining, mitotic index, and other clinicopathologic variables. Pelosi, G., Bresaola, E., Bogina, G., Pasini, F., Rodella, S., Castelli, P., Iacono, C., Serio, G., Zamboni, G. Hum. Pathol. (1996) [Pubmed]
  27. Letrozole inhibits tumor proliferation more effectively than tamoxifen independent of HER1/2 expression status. Ellis, M.J., Coop, A., Singh, B., Tao, Y., Llombart-Cussac, A., Jänicke, F., Mauriac, L., Quebe-Fehling, E., Chaudri-Ross, H.A., Evans, D.B., Miller, W.R. Cancer Res. (2003) [Pubmed]
  28. Effects of soy-protein supplementation on epithelial proliferation in the histologically normal human breast. McMichael-Phillips, D.F., Harding, C., Morton, M., Roberts, S.A., Howell, A., Potten, C.S., Bundred, N.J. Am. J. Clin. Nutr. (1998) [Pubmed]
  29. Self-renewal of human embryonic stem cells is supported by a shortened G1 cell cycle phase. Becker, K.A., Ghule, P.N., Therrien, J.A., Lian, J.B., Stein, J.L., van Wijnen, A.J., Stein, G.S. J. Cell. Physiol. (2006) [Pubmed]
  30. Dissociation between steroid receptor expression and cell proliferation in the human breast. Clarke, R.B., Howell, A., Potten, C.S., Anderson, E. Cancer Res. (1997) [Pubmed]
  31. Structure of human Ki67 FHA domain and its binding to a phosphoprotein fragment from hNIFK reveal unique recognition sites and new views to the structural basis of FHA domain functions. Li, H., Byeon, I.J., Ju, Y., Tsai, M.D. J. Mol. Biol. (2004) [Pubmed]
  32. The Ki-67 protein interacts with members of the heterochromatin protein 1 (HP1) family: a potential role in the regulation of higher-order chromatin structure. Scholzen, T., Endl, E., Wohlenberg, C., van der Sar, S., Cowell, I.G., Gerdes, J., Singh, P.B. J. Pathol. (2002) [Pubmed]
  33. Galanin and galanin receptors in human gliomas. Berger, A., Santic, R., Almer, D., Hauser-Kronberger, C., Huemer, M., Humpel, C., Stockhammer, G., Sperl, W., Kofler, B. Acta Neuropathol. (2003) [Pubmed]
  34. Both estrogen receptor alpha and estrogen receptor beta agonists enhance cell proliferation in the dentate gyrus of adult female rats. Mazzucco, C.A., Lieblich, S.E., Bingham, B.I., Williamson, M.A., Viau, V., Galea, L.A. Neuroscience (2006) [Pubmed]
  35. p16 is a robust in vivo biomarker of cellular aging in human skin. Ressler, S., Bartkova, J., Niederegger, H., Bartek, J., Scharffetter-Kochanek, K., Jansen-Dürr, P., Wlaschek, M. Aging Cell (2006) [Pubmed]
  36. PCNA/cyclin expression and BrdU uptake define different subpopulations in different cell lines. Coltrera, M.D., Gown, A.M. J. Histochem. Cytochem. (1991) [Pubmed]
  37. Topological analysis of p21WAF1/CIP1 expression in esophageal squamous dysplasia. Shirakawa, Y., Naomoto, Y., Kimura, M., Kawashima, R., Yamatsuji, T., Tamaki, T., Hamada, M., Haisa, M., Tanaka, N. Clin. Cancer Res. (2000) [Pubmed]
  38. Overexpression of human telomerase RNA is an early event in oesophageal carcinogenesis. Hiyama, T., Yokozaki, H., Kitadai, Y., Haruma, K., Yasui, W., Kajiyama, G., Tahara, E. Virchows Arch. (1999) [Pubmed]
  39. Estrogen receptor beta in breast cancer: associations between ERbeta, hormonal receptors, and other prognostic biomarkers. Choi, Y., Pinto, M. Appl. Immunohistochem. Mol. Morphol. (2005) [Pubmed]
  40. Neoadjuvant percutaneous 4-hydroxytamoxifen decreases breast tumoral cell proliferation: a prospective controlled randomized study comparing three doses of 4-hydroxytamoxifen gel to oral tamoxifen. Rouanet, P., Linares-Cruz, G., Dravet, F., Poujol, S., Gourgou, S., Simony-Lafontaine, J., Grenier, J., Kramar, A., Girault, J., Le Nestour, E., Maudelonde, T. J. Clin. Oncol. (2005) [Pubmed]
  41. Biologic markers as predictors of clinical outcome from systemic therapy for primary operable breast cancer. Chang, J., Powles, T.J., Allred, D.C., Ashley, S.E., Clark, G.M., Makris, A., Assersohn, L., Gregory, R.K., Osborne, C.K., Dowsett, M. J. Clin. Oncol. (1999) [Pubmed]
  42. Prediction of clinical outcome from primary tamoxifen by expression of biologic markers in breast cancer patients. Chang, J., Powles, T.J., Allred, D.C., Ashley, S.E., Makris, A., Gregory, R.K., Osborne, C.K., Dowsett, M. Clin. Cancer Res. (2000) [Pubmed]
  43. Expression analysis of DNA methyltransferases 1, 3A, and 3B in sporadic breast carcinomas. Girault, I., Tozlu, S., Lidereau, R., Bièche, I. Clin. Cancer Res. (2003) [Pubmed]
  44. Relationship between E-cadherin gene mutation and p53 gene mutation, p53 accumulation, Bcl-2 expression and Ki-67 staining in diffuse-type gastric carcinoma. Fricke, E., Keller, G., Becker, I., Rosivatz, E., Schott, C., Plaschke, S., Rudelius, M., Hermannstädter, C., Busch, R., Höfler, H., Becker, K.F., Luber, B. Int. J. Cancer (2003) [Pubmed]
  45. Amplification of erbB2 and erbB2 expression are superior to estrogen receptor status as risk factors for distant recurrence in pT1N0M0 breast cancer: a nationwide population-based study. Joensuu, H., Isola, J., Lundin, M., Salminen, T., Holli, K., Kataja, V., Pylkkänen, L., Turpeenniemi-Hujanen, T., von Smitten, K., Lundin, J. Clin. Cancer Res. (2003) [Pubmed]
  46. Apocrine ductal carcinoma in situ of the breast: histologic classification and expression of biologic markers. Leal, C., Henrique, R., Monteiro, P., Lopes, C., Bento, M.J., De Sousa, C.P., Lopes, P., Olson, S., Silva, M.D., Page, D.L. Hum. Pathol. (2001) [Pubmed]
  47. Expression of p53 gene product and cell proliferation marker Ki-67 in Ewing's sarcoma: correlation with clinical outcome. Amir, G., Issakov, J., Meller, I., Sucher, E., Peyser, A., Cohen, I.J., Yaniv, I., Ben Arush, M.W., Tavori, U., Kollender, Y., Ron, N., Peylan-Ramu, N. Hum. Pathol. (2002) [Pubmed]
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