• 重慶醫(yī)科大學附屬第一醫(yī)院外五科（重慶400016）;

目的 　探討乳腺癌發(fā)生、發(fā)展過程中bcl-2、bax及bad基因表達水平變化及與乳腺癌其他生物因素的相關性。
方法 　復習國內(nèi)、外相關文獻并進行綜述。
結(jié)果 　在從正常乳腺組織到乳腺癌逐漸演化的過程中凋亡抑制基因bcl-2的表達水平變化尚有待進一步研究，而凋亡促進基因bax、bad的表達水平呈遞減趨勢。bcl-2基因表達水平與乳腺癌中一些公認的正性因子如雌激素受體（ER）、孕激素受體（PR）呈正相關，與其他一些負性因子如p53、表皮生長因子受體、c-erbB-2、腋窩淋巴結(jié)轉(zhuǎn)移情況等呈負相關。bax基因的表達水平與乳腺癌ER、PR水平以及p53表達水平等無關。對于bad基因與乳腺癌其他生物因素的相關性尚未見報道。
結(jié)論 　乳腺癌中bcl-2基因表達水平的變化對乳腺癌預后以及治療的作用尚存在爭議，bad基因與乳腺癌預后的關系亦不清楚，而bax基因表達水平與乳腺癌的預后呈正相關。對于它們的研究將為我們評價乳腺癌的預后提供新的指標，為乳腺癌的治療開辟新的思路。

引用本文： 于冰,孫治君. 凋亡相關基因bcl-2、bax、bad與乳腺癌. 中國普外基礎與臨床雜志, 2007, 14(6): 739-742. doi: 復制

1. 　Hong Z, Wolfgang H, Christian De G. Bcl2-L-10, a novel anti-apoptotic member of the Bcl-2 family, blocks apoptosis in the mitochondria death pathway but not in the death receptor pathway[J]. Human Molecular Genetics, 2001; 10(21)∶2329.
2. 　Zhao Y, Li S, Childs EE, et al. Activation of pro-death Bcl-2 family proteins and mitochondria apoptosis pathway in tumor necrosis factor-alpha-induced liver injury [J]. J Biol Chem， 2001; 276(29)∶27432.
3. 　Rashmi R, Kumar S, Karunagaran D. Human colon cancer ce-lls lacking Bax resist curcumin-induced apoptosis and Bax requirement is dispensable with ectopic expression of Smac or downregulation of Bcl-XL [J]. Carcinogenesis， 2005; 26(4)∶713.
4. 　Moreno A, Figueras A, Lloveras B, et al. Apoptosis in ductal carcinoma in situ of the breast [J]. Breast J， 2001; 7(4)∶245.
5. 　Chami M, Prandini A, Campanella M, et al. Bcl-2 and Bax exert opposing effects on Ca2+ signaling, which do not depend on their putative pore-forming region [J]. J Biol Chem， 2004; 279(52)∶54581.
6. 　Buchholz TA, Davis DW, McConkey DJ, et al. Chemotherapy-induced apoptosis and Bcl-2 levels correlate with breast cancer response to chemotherapy [J]. Cancer J， 2003; 9(1)∶33.
7. 　Manion MK, Hockenbery DM. Targeting BCL-2-related proteins in cancer therapy [J]. Cancer Biol Ther， 2003; 2(4 Suppl 1)∶S105.
8. 　Andersen MH, Svane IM, Kvistborg P, et al. Immunogenicity of Bcl-2 in patients with cancer [J]. Blood， 2005; 105(2)∶728.
9. 　Del Bufalo D, Biroccio A, Trisciuoglio D, et al. Bcl-2 has differing effects on the sensitivity of breast cancer cells depending on the antineoplastic drug used [J]. Eur J Cancer， 2002; 38(18)∶2455.
10. 　Tanabe K, Kim R, Inoue H, et al. Antisense Bcl-2 and HER-2 oligonucleotide treatment of breast cancer cells enhances their sensitivity to anticancer drugs [J]. Int J Oncol， 2003; 22(4)∶875.
11. 　Joensuu H, Pylkkanen L, Toikkanen S. Bcl-2 protein expression and long-term survival in breast cancer [J]. Am J Pathol， 1994; 145(5)∶1191.
12. 　沈鎮(zhèn)宙， 邵志敏主編. 現(xiàn)代乳腺腫瘤學進展 [M]. 第1版. 上海： 上?？萍嘉墨I出版社， 2002∶353~355.
13. 　Gee JM, Robertson JF, Ellis IO, et al. Immunocytochemical localization of BCL-2 protein in human breast cancers and its relationship to a series of prognostic markers and response to endocrine therapy [J]. Int J Cancer， 1994; 59(5)∶619.
14. 　Milella M, Trisciuoglio D, Bruno T, et al. Trastuzumab down-regulates Bcl-2 expression and potentiates apoptosis induction by Bcl-2/Bcl-XL bispecific antisense oligonucleotides in HER-2 gene-amplified breast cancer cells [J]. Clin Cancer Res， 2004; 10(22)∶7747.
15. 　Linjawi A, Kontogiannea M, Halwani F, et al. Prognostic significance of p53, bcl-2, and Bax expression in early breast cancer [J]. J Am Coll Surg， 2004; 198(1)∶83.
16. 　Oltvai ZN, Milliman CL, Korsmeyer SJ. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death [J]. Cell， 1993; 74(4)∶609.
17. 　Yamaguchi H, Paranawithana SR, Lee MW, et al. Epothilone B analogue (BMS-247550)-mediated cytotoxicity through induction of Bax conformational change in human breast cancer cells [J]. Cancer Res， 2002; 62(2)∶466.
18. 　Sarkar FH, Rahman KM, Li Y. Bax translocation to mitochondria is an important event in inducing apoptotic cell death by indole-3-carbinol (I3C) treatment of breast cancer cells [J]. J Nutr， 2003; 133(7 Suppl)∶2434S.
19. 　Yu W, Sanders BG, Kline K. RRR-alpha-tocopheryl succinate-induced apoptosis of human breast cancer cells involves Bax translocation to mitochondria [J]. Cancer Res， 2003; 63(10)∶2483.
20. 　劉雪梅， 黃劍飛. bcl-2、bad在乳腺癌中表達的臨床意義 [J]. 河南腫瘤學雜志， 2005; 18(1)∶14.
21. 　Kapranos N, Karaiosifidi H, Valavanis C, et al. Prognostic significance of apoptosis related proteins Bcl-2 and Bax in node-negative breast cancer patients [J]. Anticancer Res， 1997; 17(4A)∶2499.
22. 　Schimmer AD, Hedley DW, Pham NA, et al. BAD induces apoptosis in cells over-expressing Bcl-2 or Bcl-xL without loss of mitochondrial membrane potential [J]. Leuk Lymphoma， 2001; 42(3)∶429.
23. 　Hattori T, Ookawa N, Fujita R, et al. Heterodimerization of Bcl-2 and Bcl-X(L) with Bax and Bad in colorectal cancer [J]. Acta Oncol， 2000; 39(4)∶495.
24. 　Ranger AM, Zha J, Harada H, et al. Bad-deficient mice develop diffuse large B cell lymphoma [J]. Proc Natl Acad Sci USA， 2003; 100(16)∶9324.
25. 　王曉薇， 郭炳麟， 商中華. bcl-2和bad蛋白表達與乳腺癌相關性研究 [J]. 中華普通外科雜志， 2004； 19（9）∶564.
26. 　Datta SR, Katsov A, Hu L, et al. 14-3-3 proteins and survival kinases cooperate to inactivate BAD by BH3 domain phosphorylation [J]. Mol Cell， 2000; 6(1)∶41.
27. 　Fernando RI, Wimalasena J. Estradiol abrogates apoptosis in breast cancer cells through inactivation of BAD: Ras-dependent nongenomic pathways requiring signaling through ERK and Akt [J]. Mol Biol Cell， 2004; 15(7)∶3266.
28. 　Chiu LC, Wong EY, Ooi VE. Docosahexaenoic acid from a cultured microalga inhibits cell growth and induces apoptosis by upregulating Bax/Bcl-2 ratio in human breast carcinoma MCF-7 cells [J]. Ann N Y Acad Sci， 2004; 1030∶361.
29. 　Zong WX, Lindsten T, Ross AJ, et al. BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak [J]. Genes Dev， 2001; 15(12)∶1481.
30. 　Zhang Z, Lapolla SM, Annis MG, et al. Bcl-2 homodimerization involves two distinct binding surfaces, a topographic arrangement that provides an effective mechanism for Bcl-2 to capture activated Bax [J]. J Biol Chem， 2004; 279(42)∶43920.
  1. 1. 　Hong Z, Wolfgang H, Christian De G. Bcl2-L-10, a novel anti-apoptotic member of the Bcl-2 family, blocks apoptosis in the mitochondria death pathway but not in the death receptor pathway[J]. Human Molecular Genetics, 2001; 10(21)∶2329.
  2. 2. 　Zhao Y, Li S, Childs EE, et al. Activation of pro-death Bcl-2 family proteins and mitochondria apoptosis pathway in tumor necrosis factor-alpha-induced liver injury [J]. J Biol Chem， 2001; 276(29)∶27432.
  3. 3. 　Rashmi R, Kumar S, Karunagaran D. Human colon cancer ce-lls lacking Bax resist curcumin-induced apoptosis and Bax requirement is dispensable with ectopic expression of Smac or downregulation of Bcl-XL [J]. Carcinogenesis， 2005; 26(4)∶713.
  4. 4. 　Moreno A, Figueras A, Lloveras B, et al. Apoptosis in ductal carcinoma in situ of the breast [J]. Breast J， 2001; 7(4)∶245.
  5. 5. 　Chami M, Prandini A, Campanella M, et al. Bcl-2 and Bax exert opposing effects on Ca2+ signaling, which do not depend on their putative pore-forming region [J]. J Biol Chem， 2004; 279(52)∶54581.
  6. 6. 　Buchholz TA, Davis DW, McConkey DJ, et al. Chemotherapy-induced apoptosis and Bcl-2 levels correlate with breast cancer response to chemotherapy [J]. Cancer J， 2003; 9(1)∶33.
  7. 7. 　Manion MK, Hockenbery DM. Targeting BCL-2-related proteins in cancer therapy [J]. Cancer Biol Ther， 2003; 2(4 Suppl 1)∶S105.
  8. 8. 　Andersen MH, Svane IM, Kvistborg P, et al. Immunogenicity of Bcl-2 in patients with cancer [J]. Blood， 2005; 105(2)∶728.
  9. 9. 　Del Bufalo D, Biroccio A, Trisciuoglio D, et al. Bcl-2 has differing effects on the sensitivity of breast cancer cells depending on the antineoplastic drug used [J]. Eur J Cancer， 2002; 38(18)∶2455.
  10. 10. 　Tanabe K, Kim R, Inoue H, et al. Antisense Bcl-2 and HER-2 oligonucleotide treatment of breast cancer cells enhances their sensitivity to anticancer drugs [J]. Int J Oncol， 2003; 22(4)∶875.
  11. 11. 　Joensuu H, Pylkkanen L, Toikkanen S. Bcl-2 protein expression and long-term survival in breast cancer [J]. Am J Pathol， 1994; 145(5)∶1191.
  12. 12. 　沈鎮(zhèn)宙， 邵志敏主編. 現(xiàn)代乳腺腫瘤學進展 [M]. 第1版. 上海： 上海科技文獻出版社， 2002∶353~355.
  13. 13. 　Gee JM, Robertson JF, Ellis IO, et al. Immunocytochemical localization of BCL-2 protein in human breast cancers and its relationship to a series of prognostic markers and response to endocrine therapy [J]. Int J Cancer， 1994; 59(5)∶619.
  14. 14. 　Milella M, Trisciuoglio D, Bruno T, et al. Trastuzumab down-regulates Bcl-2 expression and potentiates apoptosis induction by Bcl-2/Bcl-XL bispecific antisense oligonucleotides in HER-2 gene-amplified breast cancer cells [J]. Clin Cancer Res， 2004; 10(22)∶7747.
  15. 15. 　Linjawi A, Kontogiannea M, Halwani F, et al. Prognostic significance of p53, bcl-2, and Bax expression in early breast cancer [J]. J Am Coll Surg， 2004; 198(1)∶83.
  16. 16. 　Oltvai ZN, Milliman CL, Korsmeyer SJ. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death [J]. Cell， 1993; 74(4)∶609.
  17. 17. 　Yamaguchi H, Paranawithana SR, Lee MW, et al. Epothilone B analogue (BMS-247550)-mediated cytotoxicity through induction of Bax conformational change in human breast cancer cells [J]. Cancer Res， 2002; 62(2)∶466.
  18. 18. 　Sarkar FH, Rahman KM, Li Y. Bax translocation to mitochondria is an important event in inducing apoptotic cell death by indole-3-carbinol (I3C) treatment of breast cancer cells [J]. J Nutr， 2003; 133(7 Suppl)∶2434S.
  19. 19. 　Yu W, Sanders BG, Kline K. RRR-alpha-tocopheryl succinate-induced apoptosis of human breast cancer cells involves Bax translocation to mitochondria [J]. Cancer Res， 2003; 63(10)∶2483.
  20. 20. 　劉雪梅， 黃劍飛. bcl-2、bad在乳腺癌中表達的臨床意義 [J]. 河南腫瘤學雜志， 2005; 18(1)∶14.
  21. 21. 　Kapranos N, Karaiosifidi H, Valavanis C, et al. Prognostic significance of apoptosis related proteins Bcl-2 and Bax in node-negative breast cancer patients [J]. Anticancer Res， 1997; 17(4A)∶2499.
  22. 22. 　Schimmer AD, Hedley DW, Pham NA, et al. BAD induces apoptosis in cells over-expressing Bcl-2 or Bcl-xL without loss of mitochondrial membrane potential [J]. Leuk Lymphoma， 2001; 42(3)∶429.
  23. 23. 　Hattori T, Ookawa N, Fujita R, et al. Heterodimerization of Bcl-2 and Bcl-X(L) with Bax and Bad in colorectal cancer [J]. Acta Oncol， 2000; 39(4)∶495.
  24. 24. 　Ranger AM, Zha J, Harada H, et al. Bad-deficient mice develop diffuse large B cell lymphoma [J]. Proc Natl Acad Sci USA， 2003; 100(16)∶9324.
  25. 25. 　王曉薇， 郭炳麟， 商中華. bcl-2和bad蛋白表達與乳腺癌相關性研究 [J]. 中華普通外科雜志， 2004； 19（9）∶564.
  26. 26. 　Datta SR, Katsov A, Hu L, et al. 14-3-3 proteins and survival kinases cooperate to inactivate BAD by BH3 domain phosphorylation [J]. Mol Cell， 2000; 6(1)∶41.
  27. 27. 　Fernando RI, Wimalasena J. Estradiol abrogates apoptosis in breast cancer cells through inactivation of BAD: Ras-dependent nongenomic pathways requiring signaling through ERK and Akt [J]. Mol Biol Cell， 2004; 15(7)∶3266.
  28. 28. 　Chiu LC, Wong EY, Ooi VE. Docosahexaenoic acid from a cultured microalga inhibits cell growth and induces apoptosis by upregulating Bax/Bcl-2 ratio in human breast carcinoma MCF-7 cells [J]. Ann N Y Acad Sci， 2004; 1030∶361.
  29. 29. 　Zong WX, Lindsten T, Ross AJ, et al. BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak [J]. Genes Dev， 2001; 15(12)∶1481.
  30. 30. 　Zhang Z, Lapolla SM, Annis MG, et al. Bcl-2 homodimerization involves two distinct binding surfaces, a topographic arrangement that provides an effective mechanism for Bcl-2 to capture activated Bax [J]. J Biol Chem， 2004; 279(42)∶43920.