乳腺癌分子分型与远处转移时间及部位的分析
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摘要
目的:了解乳腺癌患者远处转移部位及时间在各乳腺癌分子亚型间的分布,探讨其中可能的规律,为乳腺癌预后评估及个体化远处转移的筛查提供依据。
方法:回顾分析2000年1月至2009年1月在我院确诊为乳腺癌的女性可手术患者,包括非我院首诊,但有石蜡块为病理依据的患者,入组患者标准:均接受根治术或改良根治术,并经过正规周期化疗、放疗,内分泌治疗1年以上。收集并完善所有病例的雌激素受体(ER)、孕激素受体(PR)、人类表皮生长因子受体2(HER2)的免疫组化检测结果,通过随诊、电话、信件及上门随访等多种方式,追踪了解患者有无远处转移及发生的时间和部位。以发生远处转移为随访终点,将发生远处转移的患者依首发转移部位分为内脏转移和非内脏转移两组,分析乳腺癌各分子亚型患者首次远处转移部位和时间的风险分布。采用非参数检验分析各组间转移率差异和各分子亚型远处转移的部位风险分布,并与以T(肿瘤大小)、N(淋巴结状态)为分组依据的结果进行比较;采用Cox风险函数法,分析各分子亚型远处转移的时间风险分布,估计半年事件风险。所采用统计软件均为SPSS13.0.
结果:
1共129例发生远处转移的乳腺癌患者,首次为内脏转移78例,非内脏转移51例,内脏转移患者较非内脏转移的患者无远处转移生存率低(P =0.04);
2 luminalA型患者非内脏转移率较内脏转移率高(P =0.06),HER2过表达型和basal-like型患者内脏转移率较非内脏转移率高(P =0.01、P =0.001);
3 T1期肿瘤患者非内脏转移率较高(P =0.032),T3-4期肿瘤患者内脏转移率较高,(P =0.001);以N为分组依据的患者,淋巴结阳性患者总转移率较高,(P=0.03),但各组患者内脏转移率和非内脏转移率无明显差异(P =0.10)。
4转移事件的风险分布(以半年为单位):各分子亚型的复发风险函数曲线显示:luminalA型曲线低平,提示转移风险低,且高峰出现时间较晚,basal-like型第一高峰出现时间早,峰值高,提示此型乳腺癌转移风险高;在本组所有患者中,超过50%的转移发生在术后3年内,术后2.5年为第一复发转移高峰,术后7年出现第二高峰;内脏组风险函数曲线显示:术后1.5年为第一高峰,峰值较高,持续时间长,术后7年出现第二高峰;非内脏组风险函数曲线显示:术后3年出现首峰,较内脏转移组稍迟,峰值较低,持续时间较短。
结论:乳腺癌分子分型作为患者预后评估的重要工具,能更准确评估患者术后远处转移的时间和部位分布,是TNM分期法的重要补充,有助患者术后远处转移的时间和部位个体化筛查。
Objective:
Find out the risk distribution of breast cancer for time and location of distant metastasis in molecular typing, and try to find the law may exist,to provide evidence for patients for assessing the prognosis and individual screening of distant metastasis.
Methods:
We study retrospectively the female patients who were diagnosed as invasive ductal breast cancer in our hospital from January 2000 to January 2009, Including the patients who got the first treatment outside hospital, but were clarified for their pathological diagnosis by our Department of Pathology consultation with paraffin sections.and detect the ER, PR, HER2 expressed in the paraffin sections,then track these patients for survival by follow-up means.The patients with distant metastasis are divided into visceral metastasis and non-visceral metastasis with the first transfer site as standard,for analysing the distribution in molecular typing and the time of the first site of distant metastasis.We analyze the difference of transfer rate between groups by Non-parametric test and estimate hazard function for every six months by COX hazard function estimate, then test the difference survival of groups by life tables.The statistical software adpoted is SPSS13.0.
Results:
1 There are 129 patients encountered distant metastasis who were diagnosed as breast invasive ductal carcinoma in our hospital from January 2000 to January 2009 ,including 78 patients with visceral metastasis ,and 51 patients with non-visceral metastasis. The survival rate of patients with visceral metastasis is lower than those with non-visceral metastasis;
2 The rate of visceral metastasis for patients’who belong to luminalA type is lower than that of non-visceral metastasis(P =0.06),and the rates of visceral metastasis for patients who belong to HER2 type and basal-like type are higher than that of non-visceral metastasis(P =0.01、P =0.001);
3 The patients whose tumor belong to T1 have higher rate of distant metastasis to non-viscera(P =0.032),and those belong to T3-4 have higher rate of diatant metastasis to viscara(P =0.001);when we divide these patients by node state,we find that patients with different node state have different rate of distant metastasis,but no difference between viscara and non-viscera when in the same state(P =0.10).
4 The risk distribution of transfer events for every six months: the risk function curve of molecular types shows that, the peak of luminalA type is lowest,delayed, prompt that the risk of distant metastasis is low in 3 years after the operation,and the basal-like’s is highest,advanced, prompt that the risk of distant metastasis is high in 3 years after the operation,.More than 50% of the transfers occurred at the 3thyear after the operation,the first metastasis peak occurred at the 2.5thyear after the operation,and the second occurs at the 7th year.The Visceral metastasis risk function curve shows that, the first metastasis peak occured at the 1.5th year,and the peak is higher,The non-visceral metastasis risk function curve shows that the first metastasis peak is delayed than the former,and the peak is lower. Conclusions:
As an important tool for assessing the prognosis of patients,molecular typing of breast cancer can assess the patients of diatant metastasis for time and location more accurately,is an important complement for TNM method,for helping the individual screening of patients for distant metastasis.
方法:回顾分析2000年1月至2009年1月在我院确诊为乳腺癌的女性可手术患者,包括非我院首诊,但有石蜡块为病理依据的患者,入组患者标准:均接受根治术或改良根治术,并经过正规周期化疗、放疗,内分泌治疗1年以上。收集并完善所有病例的雌激素受体(ER)、孕激素受体(PR)、人类表皮生长因子受体2(HER2)的免疫组化检测结果,通过随诊、电话、信件及上门随访等多种方式,追踪了解患者有无远处转移及发生的时间和部位。以发生远处转移为随访终点,将发生远处转移的患者依首发转移部位分为内脏转移和非内脏转移两组,分析乳腺癌各分子亚型患者首次远处转移部位和时间的风险分布。采用非参数检验分析各组间转移率差异和各分子亚型远处转移的部位风险分布,并与以T(肿瘤大小)、N(淋巴结状态)为分组依据的结果进行比较;采用Cox风险函数法,分析各分子亚型远处转移的时间风险分布,估计半年事件风险。所采用统计软件均为SPSS13.0.
结果:
1共129例发生远处转移的乳腺癌患者,首次为内脏转移78例,非内脏转移51例,内脏转移患者较非内脏转移的患者无远处转移生存率低(P =0.04);
2 luminalA型患者非内脏转移率较内脏转移率高(P =0.06),HER2过表达型和basal-like型患者内脏转移率较非内脏转移率高(P =0.01、P =0.001);
3 T1期肿瘤患者非内脏转移率较高(P =0.032),T3-4期肿瘤患者内脏转移率较高,(P =0.001);以N为分组依据的患者,淋巴结阳性患者总转移率较高,(P=0.03),但各组患者内脏转移率和非内脏转移率无明显差异(P =0.10)。
4转移事件的风险分布(以半年为单位):各分子亚型的复发风险函数曲线显示:luminalA型曲线低平,提示转移风险低,且高峰出现时间较晚,basal-like型第一高峰出现时间早,峰值高,提示此型乳腺癌转移风险高;在本组所有患者中,超过50%的转移发生在术后3年内,术后2.5年为第一复发转移高峰,术后7年出现第二高峰;内脏组风险函数曲线显示:术后1.5年为第一高峰,峰值较高,持续时间长,术后7年出现第二高峰;非内脏组风险函数曲线显示:术后3年出现首峰,较内脏转移组稍迟,峰值较低,持续时间较短。
结论:乳腺癌分子分型作为患者预后评估的重要工具,能更准确评估患者术后远处转移的时间和部位分布,是TNM分期法的重要补充,有助患者术后远处转移的时间和部位个体化筛查。
Objective:
Find out the risk distribution of breast cancer for time and location of distant metastasis in molecular typing, and try to find the law may exist,to provide evidence for patients for assessing the prognosis and individual screening of distant metastasis.
Methods:
We study retrospectively the female patients who were diagnosed as invasive ductal breast cancer in our hospital from January 2000 to January 2009, Including the patients who got the first treatment outside hospital, but were clarified for their pathological diagnosis by our Department of Pathology consultation with paraffin sections.and detect the ER, PR, HER2 expressed in the paraffin sections,then track these patients for survival by follow-up means.The patients with distant metastasis are divided into visceral metastasis and non-visceral metastasis with the first transfer site as standard,for analysing the distribution in molecular typing and the time of the first site of distant metastasis.We analyze the difference of transfer rate between groups by Non-parametric test and estimate hazard function for every six months by COX hazard function estimate, then test the difference survival of groups by life tables.The statistical software adpoted is SPSS13.0.
Results:
1 There are 129 patients encountered distant metastasis who were diagnosed as breast invasive ductal carcinoma in our hospital from January 2000 to January 2009 ,including 78 patients with visceral metastasis ,and 51 patients with non-visceral metastasis. The survival rate of patients with visceral metastasis is lower than those with non-visceral metastasis;
2 The rate of visceral metastasis for patients’who belong to luminalA type is lower than that of non-visceral metastasis(P =0.06),and the rates of visceral metastasis for patients who belong to HER2 type and basal-like type are higher than that of non-visceral metastasis(P =0.01、P =0.001);
3 The patients whose tumor belong to T1 have higher rate of distant metastasis to non-viscera(P =0.032),and those belong to T3-4 have higher rate of diatant metastasis to viscara(P =0.001);when we divide these patients by node state,we find that patients with different node state have different rate of distant metastasis,but no difference between viscara and non-viscera when in the same state(P =0.10).
4 The risk distribution of transfer events for every six months: the risk function curve of molecular types shows that, the peak of luminalA type is lowest,delayed, prompt that the risk of distant metastasis is low in 3 years after the operation,and the basal-like’s is highest,advanced, prompt that the risk of distant metastasis is high in 3 years after the operation,.More than 50% of the transfers occurred at the 3thyear after the operation,the first metastasis peak occurred at the 2.5thyear after the operation,and the second occurs at the 7th year.The Visceral metastasis risk function curve shows that, the first metastasis peak occured at the 1.5th year,and the peak is higher,The non-visceral metastasis risk function curve shows that the first metastasis peak is delayed than the former,and the peak is lower. Conclusions:
As an important tool for assessing the prognosis of patients,molecular typing of breast cancer can assess the patients of diatant metastasis for time and location more accurately,is an important complement for TNM method,for helping the individual screening of patients for distant metastasis.
引文
1 Fisher B, Jeong JH, Bryant J et al. Treatment of lymph-node-negative oestrogen- receptor-positive breast cancer: long-term findings from National Surgical Adjuv-ant Breast and Bowel Projeet randomized clinieal trials[J]. Lancet, 2004, 364: 858-868.
2 Brown JM, Giaccia AJ.The unique physiology of solid tumors:opportunities and problems for cancer therapy[J]. Cancer Res,1998,58(7):1408-1416.
3 Minn AJ, Kang Y, Serganova I, Gupta GP, Giri DD, Doubrovin M,et al. Distinct organ-specific metastatic potential of individualbreast cancer cells and primary tumors[J]. J Clin Invest 2005,115.
4 Mack MG,Straub R,Eichler K,et al.Breast cancer metastasis in liver:laser-induce dinterstitial thermotherapy-local tumor control rate and survival data[J],Radio- logy ,2004,233(2):400-409.
5 Elias D,Lasser P,Spielmann M,et al.Surgical and chemotherapeutic treatment of hepatic metastasis from carcinoma of the breast[J].Surg Gynecol Obstet,1992, 172(6):461-464.
6 Bertucci F,Finetti P,Cervera N. How different are luminal A and basal breast cancers[J]? Int. J. Cancer,2009,124:1338–1348.
7 Kovacs CS. Calcium and Bone Metabolism During Pregnancy and Lactation[J]. J Mammary Gland Biol Neoplasia 2005,10 2:105–18.
8 VanHouten JN, Dann P, Stewart AF, Watson CJ, Pollak M,Karaplis AC, et al. Mammary-specific deletion of parathyroid hormone-related protein preserves bone mass during lactation[J]. JClin Invest 2003,112 9:1429–36.
9 Jones DH, Nakashima T, Sanchez OH, Kozieradzki I, Komarova SV, Sarosi I, et al. Regulation of cancer cell migration and bone metastasis by RANKL[J]. Nature 2006,440 7084:692–6.
10 Wilke LG,Giuliano A.Sentinel lymph node biopsy in patients with early-stage breast cancer: status of the National Clinical Trials. Surg Clin North AM,2003 Aug;83(4),901-10.
11 Mitsuru K,Masataka Y,Fujio K,et al .What do breast cancer patients benefit from staging bone scntigraphy[J]? Jpn J Clinoncol,2001,21(6):263-269 .
12 Carey LA,Perou CM,Livasy CA,el a1.Race,breast cancer subtypes and survival in the Carolina Breast Cancer Study.JAMA,2006,295:2492-2502.
13 I'tier N,Tutt,Ashwomb A.Hallmarks of“BRCAness”in sporadic cancers[J].Nat Rev Cancer,2004,4:814-819.
14 Minn AJ,Gupta GP,Siegel PM,et al.Genes that mediate breast cancer metastasis to lung[J].Nature,2005,436:518-524.
15 Haffy BG,Yang Q,Reiss M,et al.Locoreginal relapse and distant metastasis in conservatively managed triple negative early-stage breast cancer[J].Clin Oncol, 2006,24:5652-5657.
16 Lin NU, Winer EO.Brain metastasis:the HER2 paradigm[J].Clin CancerRes,2007, 13(6):1648-1655.
17 Carey LA,Iees EC,Sawyer L,et a1.Triple negative paradox:primary tumor chemosensitivity of breast cancer subtypes[J].Clin Cancer Res,2007,13:2329- 2334.
18 Demicheli R,Valagussa P,Bonadonna G.Double peaked time distribution of mortality for breast cancer patients undergoing mastectomy[J].Breat Cancer Res Treat,2002,75(2):127-134.
19 Yin W,Di G,Zhou L,Lu J.Time-varying pattern of recurrence risk for Chinese breast cancer patients[J]. Breast Cancer Res Treat. 2009Jul,116(1):209-210.
20 Gao F,Tan SB,Machin D,Wong NS.Confirmation of double-peaked time distribu- tion of mortality among Asian breast cancer patients in a population-based study [J]. Breast Cancer Res, 2007,9(2):R21.
21 Muller A, Homey B, Soto H. Involvement of chemokine receptors in breast cancer metastasis[J].Nature ,2001,V410N6824:50-56.
22 Demicheli R,Beganzoli E,Ardoino L,Boracchi P.Recurrence and mortality dyna -mics for breast cancer patients undergoing mastectomy according to estrogen receptor status: different mortality but similar recurrence[J].Cancer Sci,2010Mar, 101(3):826-839.
1 Chambers AF, Groom AC, MacDonald IC. Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2002,28:563–72.
2 Fidler IJ. Selection of successive tumour lines for metastasis. NatNew Biol 1973,242118:148–9.
3 Kang Y. Functional genomic analysis of cancer metastasis:biologic insights and clinical implications. Expert Rev Mol Diagn2005,5 3:385–95.
4 Minn AJ, Kang Y, Serganova I, Gupta GP, Giri DD, Doubrovin M,et al. Distinct organ-specific metastatic potential of individualbreast cancer cells and primary tumors. J Clin Invest 2005,115.
5 Paget S. Distribution of secondary growths in cancer of the breast.Lancet 1889,1:571–3.
6 Fidler IJ. The pathogenesis of cancer metastasis: the‘seed and soil’hypothesis revisited. Nat Rev Cancer 2003,36:453–8.
7 Kang Y, He W, Tulley S, Gupta GP, Serganova I, Chen CR, et al.Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway. Proc Natl Acad Sci USA 2005,10239:13909–14.
8 Harada S, Rodan GA. Control of osteoblast function and regulation of bone mass. Nature 2003,4236937:349–55.
9 Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature 2003,4236937:337–42.
10 Steeg PS. Tumor metastasis: mechanistic insights and clinical challenges. Nat Med 2006,128:895–904.
11 Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer 2002,28:584–93.
12 Ohshiba T, Miyaura C, Ito A. Role of prostaglandin E produced by osteoblasts in osteolysis due to bone metastasis. Biochem Biophys Res Commun 2003,300 4:957–64.
13 Gupta GP, Massague J. Cancer Metastasis: Building a Framework.Cell 2006,127 4:679–95.
14 Kovacs CS. Calcium and Bone Metabolism During Pregnancy andLactation. J Mammary Gland Biol Neoplasia 2005;102:105–18.
15 VanHouten JN, Dann P, Stewart AF, Watson CJ, Pollak M,Karaplis AC, et al. Mammary-specific deletion of parathyroid hormone-related protein preserves bone mass during lactation. JClin Invest 2003,1129:1429–36.
16 Jones DH, Nakashima T, Sanchez OH, Kozieradzki I, Komarova SV, Sarosi I, et al. Regulation of cancer cell migration and bone metastasis by RANKL. Nature 2006,4407084:692–6.
17 Barnes GL, Hebert KE, Kamal M, Javed A, Einhorn TA, Lian JB,et al. Fidelity of Runx2 activity in breast cancer cells is required for the generation of metastases-associated osteolytic disease.Cancer Res 2004,6413:4506–13.
18 Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, et al.Involvement of chemokine receptors in breast cancer metastasis.Nature 2001,410 6824:50–6.
19 Cheng H-C, Abdel-Ghany M, Elble RC, Pauli BU. Lung endothelial ipeptidyl peptidaseD IV promotes adhesion and metastasis of rat breast cancer cells via tumor cell surface associated fibronectin. J Biol Chem 1998,27337:24207–15.
20 Minn AJ, Gupta GP, Siegel PM, Bos PD, Shu W, Giri DD, et al.Genes that mediate breast cancer metastasis to lung. Nature2005,4367050:518–24.
21 Jiang WG, Matsumoto K, NakamuraT, ebrary Inc. Growth factors and their receptors in cancer metastasis. Dordrecht: Kluwer; 2001.
22 Park BK, Zhang H, Zeng Q, Dai J, Keller ET, Giordano T, et al.NF-kappaB in breast cancer cells promotes osteolytic bone metastasis by inducing osteoclastogenesis via GM-CSF. Nat Med 2007,13 1:62–9.
23 Siegel PM, Shu W, Cardiff RD, Muller WJ, Massague J.Transforming growth factor beta signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis.Proc Natl Acad Sci USA 2003,10014:8430–5.
24 Weil RJ, Palmieri DC, Bronder JL, Stark AM, Steeg PS. Breast cancer metastasis to the central nervous system. Am J Pathol2005,1674:913–20.
25 Kim LS, Huang S, Lu W, Lev DC, Price JE. Vascular endothelialgrowth factor expression promotes the growth of breast cancerbrain metastases in nude mice. Clin Exp Metastasis 2004,212:107–18.
26 Stessels F, Van den Eynden G, Van der Auwera I, Salgado R, Vanden Heuvel E, Harris AL, et al. Breast adenocarcinoma liver metastases, in contrast to colorectal cancer liver metastases,display a non-angiogenic growth pattern that preserves the stroma and lacks hypoxia. Br J Cancer 2004,907:1429–36.
27 Yoneda T, Williams PJ, Hiraga T, Niewolna M, Nishimura R. A bone-seeking clone exhibits different biological properties from the MDA-MB-231 parental human breast cancer cells and a brain seeking clone in vivo and in vitro. J Bone Miner Res 2001,168:1486–95.
28 Price JE. Metastasis from human breast cancer cell lines. Breast Cancer Res Treat 1996:39.
2 Brown JM, Giaccia AJ.The unique physiology of solid tumors:opportunities and problems for cancer therapy[J]. Cancer Res,1998,58(7):1408-1416.
3 Minn AJ, Kang Y, Serganova I, Gupta GP, Giri DD, Doubrovin M,et al. Distinct organ-specific metastatic potential of individualbreast cancer cells and primary tumors[J]. J Clin Invest 2005,115.
4 Mack MG,Straub R,Eichler K,et al.Breast cancer metastasis in liver:laser-induce dinterstitial thermotherapy-local tumor control rate and survival data[J],Radio- logy ,2004,233(2):400-409.
5 Elias D,Lasser P,Spielmann M,et al.Surgical and chemotherapeutic treatment of hepatic metastasis from carcinoma of the breast[J].Surg Gynecol Obstet,1992, 172(6):461-464.
6 Bertucci F,Finetti P,Cervera N. How different are luminal A and basal breast cancers[J]? Int. J. Cancer,2009,124:1338–1348.
7 Kovacs CS. Calcium and Bone Metabolism During Pregnancy and Lactation[J]. J Mammary Gland Biol Neoplasia 2005,10 2:105–18.
8 VanHouten JN, Dann P, Stewart AF, Watson CJ, Pollak M,Karaplis AC, et al. Mammary-specific deletion of parathyroid hormone-related protein preserves bone mass during lactation[J]. JClin Invest 2003,112 9:1429–36.
9 Jones DH, Nakashima T, Sanchez OH, Kozieradzki I, Komarova SV, Sarosi I, et al. Regulation of cancer cell migration and bone metastasis by RANKL[J]. Nature 2006,440 7084:692–6.
10 Wilke LG,Giuliano A.Sentinel lymph node biopsy in patients with early-stage breast cancer: status of the National Clinical Trials. Surg Clin North AM,2003 Aug;83(4),901-10.
11 Mitsuru K,Masataka Y,Fujio K,et al .What do breast cancer patients benefit from staging bone scntigraphy[J]? Jpn J Clinoncol,2001,21(6):263-269 .
12 Carey LA,Perou CM,Livasy CA,el a1.Race,breast cancer subtypes and survival in the Carolina Breast Cancer Study.JAMA,2006,295:2492-2502.
13 I'tier N,Tutt,Ashwomb A.Hallmarks of“BRCAness”in sporadic cancers[J].Nat Rev Cancer,2004,4:814-819.
14 Minn AJ,Gupta GP,Siegel PM,et al.Genes that mediate breast cancer metastasis to lung[J].Nature,2005,436:518-524.
15 Haffy BG,Yang Q,Reiss M,et al.Locoreginal relapse and distant metastasis in conservatively managed triple negative early-stage breast cancer[J].Clin Oncol, 2006,24:5652-5657.
16 Lin NU, Winer EO.Brain metastasis:the HER2 paradigm[J].Clin CancerRes,2007, 13(6):1648-1655.
17 Carey LA,Iees EC,Sawyer L,et a1.Triple negative paradox:primary tumor chemosensitivity of breast cancer subtypes[J].Clin Cancer Res,2007,13:2329- 2334.
18 Demicheli R,Valagussa P,Bonadonna G.Double peaked time distribution of mortality for breast cancer patients undergoing mastectomy[J].Breat Cancer Res Treat,2002,75(2):127-134.
19 Yin W,Di G,Zhou L,Lu J.Time-varying pattern of recurrence risk for Chinese breast cancer patients[J]. Breast Cancer Res Treat. 2009Jul,116(1):209-210.
20 Gao F,Tan SB,Machin D,Wong NS.Confirmation of double-peaked time distribu- tion of mortality among Asian breast cancer patients in a population-based study [J]. Breast Cancer Res, 2007,9(2):R21.
21 Muller A, Homey B, Soto H. Involvement of chemokine receptors in breast cancer metastasis[J].Nature ,2001,V410N6824:50-56.
22 Demicheli R,Beganzoli E,Ardoino L,Boracchi P.Recurrence and mortality dyna -mics for breast cancer patients undergoing mastectomy according to estrogen receptor status: different mortality but similar recurrence[J].Cancer Sci,2010Mar, 101(3):826-839.
1 Chambers AF, Groom AC, MacDonald IC. Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2002,28:563–72.
2 Fidler IJ. Selection of successive tumour lines for metastasis. NatNew Biol 1973,242118:148–9.
3 Kang Y. Functional genomic analysis of cancer metastasis:biologic insights and clinical implications. Expert Rev Mol Diagn2005,5 3:385–95.
4 Minn AJ, Kang Y, Serganova I, Gupta GP, Giri DD, Doubrovin M,et al. Distinct organ-specific metastatic potential of individualbreast cancer cells and primary tumors. J Clin Invest 2005,115.
5 Paget S. Distribution of secondary growths in cancer of the breast.Lancet 1889,1:571–3.
6 Fidler IJ. The pathogenesis of cancer metastasis: the‘seed and soil’hypothesis revisited. Nat Rev Cancer 2003,36:453–8.
7 Kang Y, He W, Tulley S, Gupta GP, Serganova I, Chen CR, et al.Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway. Proc Natl Acad Sci USA 2005,10239:13909–14.
8 Harada S, Rodan GA. Control of osteoblast function and regulation of bone mass. Nature 2003,4236937:349–55.
9 Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature 2003,4236937:337–42.
10 Steeg PS. Tumor metastasis: mechanistic insights and clinical challenges. Nat Med 2006,128:895–904.
11 Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer 2002,28:584–93.
12 Ohshiba T, Miyaura C, Ito A. Role of prostaglandin E produced by osteoblasts in osteolysis due to bone metastasis. Biochem Biophys Res Commun 2003,300 4:957–64.
13 Gupta GP, Massague J. Cancer Metastasis: Building a Framework.Cell 2006,127 4:679–95.
14 Kovacs CS. Calcium and Bone Metabolism During Pregnancy andLactation. J Mammary Gland Biol Neoplasia 2005;102:105–18.
15 VanHouten JN, Dann P, Stewart AF, Watson CJ, Pollak M,Karaplis AC, et al. Mammary-specific deletion of parathyroid hormone-related protein preserves bone mass during lactation. JClin Invest 2003,1129:1429–36.
16 Jones DH, Nakashima T, Sanchez OH, Kozieradzki I, Komarova SV, Sarosi I, et al. Regulation of cancer cell migration and bone metastasis by RANKL. Nature 2006,4407084:692–6.
17 Barnes GL, Hebert KE, Kamal M, Javed A, Einhorn TA, Lian JB,et al. Fidelity of Runx2 activity in breast cancer cells is required for the generation of metastases-associated osteolytic disease.Cancer Res 2004,6413:4506–13.
18 Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, et al.Involvement of chemokine receptors in breast cancer metastasis.Nature 2001,410 6824:50–6.
19 Cheng H-C, Abdel-Ghany M, Elble RC, Pauli BU. Lung endothelial ipeptidyl peptidaseD IV promotes adhesion and metastasis of rat breast cancer cells via tumor cell surface associated fibronectin. J Biol Chem 1998,27337:24207–15.
20 Minn AJ, Gupta GP, Siegel PM, Bos PD, Shu W, Giri DD, et al.Genes that mediate breast cancer metastasis to lung. Nature2005,4367050:518–24.
21 Jiang WG, Matsumoto K, NakamuraT, ebrary Inc. Growth factors and their receptors in cancer metastasis. Dordrecht: Kluwer; 2001.
22 Park BK, Zhang H, Zeng Q, Dai J, Keller ET, Giordano T, et al.NF-kappaB in breast cancer cells promotes osteolytic bone metastasis by inducing osteoclastogenesis via GM-CSF. Nat Med 2007,13 1:62–9.
23 Siegel PM, Shu W, Cardiff RD, Muller WJ, Massague J.Transforming growth factor beta signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis.Proc Natl Acad Sci USA 2003,10014:8430–5.
24 Weil RJ, Palmieri DC, Bronder JL, Stark AM, Steeg PS. Breast cancer metastasis to the central nervous system. Am J Pathol2005,1674:913–20.
25 Kim LS, Huang S, Lu W, Lev DC, Price JE. Vascular endothelialgrowth factor expression promotes the growth of breast cancerbrain metastases in nude mice. Clin Exp Metastasis 2004,212:107–18.
26 Stessels F, Van den Eynden G, Van der Auwera I, Salgado R, Vanden Heuvel E, Harris AL, et al. Breast adenocarcinoma liver metastases, in contrast to colorectal cancer liver metastases,display a non-angiogenic growth pattern that preserves the stroma and lacks hypoxia. Br J Cancer 2004,907:1429–36.
27 Yoneda T, Williams PJ, Hiraga T, Niewolna M, Nishimura R. A bone-seeking clone exhibits different biological properties from the MDA-MB-231 parental human breast cancer cells and a brain seeking clone in vivo and in vitro. J Bone Miner Res 2001,168:1486–95.
28 Price JE. Metastasis from human breast cancer cell lines. Breast Cancer Res Treat 1996:39.