Apoptosis Related Gene bcl-2， bax， bad and Breast Cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

YU Bing , SUN Zhijun

Department of General Surgery, The First Affiliated Hospital, Chongqing University of Medical Science, Chongqing 400016, China;

Corresponding author：

Keywords：

bcl-2 gene; bax gene; bad gene; Apoptosis; Breast cancer

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Objective　 To review the relationship between the expression levels of bcl-2, bax and bad gene and other biological factors of breast cancer in the growth and development of breast cancer.
Methods 　Related literatures were summarized and reviewed.
Results 　The expression level change of antiapoptosis gene bcl-2 was still under research and the expression levels of apoptosis gene bax and bad were down-regulated progressively in the evolution from benign breast tissue to breast cancer tissue. The expression level of bcl-2 had positive correlation with some positive factors in breast cancer such as estrogen receptor （ER） and progesterone receptor (PR), while it had negative correlation with some negative factors such as p53, EGFR, c-erbB-2 and lymph node metastasis. The levels of ER, PR and the expression level of p53 of breast cancer had no relationship with the expression level of bax. Up to now there was no report about the relationship between the expression level of bad and other biological factors of breast cancer.
Conclusion 　The role of altered expression level of bcl-2, in the treatment and prognosis of breast cancer is still controversial, and the relationship between the expression of bad and the prognosis of breast cancer is still unknown, but expression level of bax is correlated positively with the prognosis of breast cancer. Research on these genes can provide us some new index to evaluate the prognosis of breast cancer and new ideas on treatment of breast cancer including gene therapy.

Citation： YU Bing,SUN Zhijun. Apoptosis Related Gene bcl-2， bax， bad and Breast Cancer. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2007, 14(6): 739-742. doi: Copy

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.	沈镇宙，邵志敏主编. 现代乳腺肿瘤学进展 [M]. 第1版. 上海：上海科技文献出版社， 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.	刘雪梅，黄剑飞. bcl-2、bad在乳腺癌中表达的临床意义 [J]. 河南肿瘤学杂志， 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.	王晓薇，郭炳麟，商中华. bcl-2和bad蛋白表达与乳腺癌相关性研究 [J]. 中华普通外科杂志， 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. 　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. 　沈镇宙，邵志敏主编. 现代乳腺肿瘤学进展 [M]. 第1版. 上海：上海科技文献出版社， 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. 　刘雪梅，黄剑飞. bcl-2、bad在乳腺癌中表达的临床意义 [J]. 河南肿瘤学杂志， 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. 　王晓薇，郭炳麟，商中华. bcl-2和bad蛋白表达与乳腺癌相关性研究 [J]. 中华普通外科杂志， 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.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Apoptosis Related Gene bcl-2， bax， bad and Breast Cancer

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