Abstract
Capsaicin-induced inactivation of sensory neurons has been reported to enhance metastasis of a murine breast cancer cell line, specifically enhancing mycocardial metastases. Here we characterized changes in gene expression patterns in primary tumors which developed in capsaicin-treated vs. control mice. We identified a small cohort of genes (17) which all showed significant decreases in expression levels. All of the identified genes have been linked to cell growth, differentiation, and/or cancer progression. Three representative genes, Caspase-7 (an executor of apoptosis), ADAM-10 (A Disintegrin and Metalloprotease), and Elk-3 (a transcriptional repressor of the ternary factor subfamily of the Ets factors) were further investigated. All three showed dramatic downregulation at the protein level in primary tumors from capsaicin-treated animals compared with control (vehicle-treated) animals, and their expression was also lost in cell culture. Elk-3 and Caspase-7 were not expressed in vitro in cultured cell lines, suggesting that their expression was induced by the tumor microenvironment. Loss of Caspase-7 expression can be expected to result in loss of function of apoptotic pathways. At first glance, loss of ADAM-10 expression would be expected to result in decreased invasive capability, due to loss of matrix metalloprotease activity. However, just the opposite appears to be true. We found that ADAM-10 actually hydrolyzes Substance P. Specifically ADAM-10 produces the same growth-inhibitory products from Substance P (i.e., SP (1–7)) that Neprilysin does, so that loss of ADAM-10 expression actually results in loss of production of growth inhibitory peptides from Substance P. Similarly, ADAM-10 also efficiently hydrolyzes Calcitonin Gene-Related Peptide, which may act in concert with Substance P. Finally, overactivity of Ets transcriptional suppressor functions has been linked to inhibition of tumorigenesis (e.g., Erf and Mef), and in addition loss of Elk-3 expression might also be be linked to tumorigenesis via loss of its putative anti-inflammatory activities. There is anecdotal evidence in the literature to indicate that the rest of the down-regulated genes may also contribute to development of a more aggressive phenotype in this breast cancer model.
Similar content being viewed by others
Abbreviations
- ADAM:
-
A Disintegrin And Metalloprotease
- CGRP:
-
Calcitonin Gene-Related Peptide
- DPPIV:
-
Dipeptidyl peptidase IV
- GEAE:
-
Gene Array Expression Analysis
- MMP:
-
matrix metalloprotease
- NOS2:
-
nitric oxide synthase 2
- SP:
-
Substance P
- 4THMpc:
-
4T1 cells after metastasis to heart muscle in capsaicin-treated animals
References
2003 Marimastat: BB2516, TA2516. Drugs Res Dev 4:198–203
Ambs S, Ogunfusika M, Merriam W, Bennett W, Billiar T, Harris C (1998) Up-regulation of inducible nitric oxide synthase expression in cancer-prone p53 knockout mice. Proc Natl Acad Sci(USA) 95:8823–8828
Arai Y, Hosoda F, Kobayashi H, Arai K, Hayashi Y, Kamada N, Kaneko Y, Ohki M (1997) The inv(11)(p15q22) chromosome translocation of de novo and therapy-related myeloid malignancies results in fusion of the nucleoporin gene, NUP98, with the putative RNA helicase gene DDX10. Blood 89:3936–3944
Aslakson C, Miller F (1992) Selective events in the metastatic process defined by analysis of the sequential dissemination of subpopulations of a mouse mammary tumor. Cancer Res 52:1399–405
Barrett J, Puglia M, Singh G, Tozer R (2002) Expression of Ets-related transcription factors and matrix metalloproteinase genes in human breast cancer cells. Breast Can Res Treat 72:227–232
Bedford M, Chan D, Leder P (1997) FBP WW domains and the Abl SH3 domain bind to a specific class of proline-rich ligands. EMBO J 16:2376–2383
Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Royal Stat Soc Series B 57:289–300
Bieche I, Latil A, Parfait B, Vidaud D, Laurendeau I, Lidereau R, Cussenot O, Vidaud M (2003) CGA gene (coding for the alpha subunit of glycoprotein hormones) overexpression in ER a-positive prostate tumors. Eur Urol 41:335–341
Bieche I, Parfait B, Nogues C, Andrieu C, Vidaud D, Spyratos F, Lidereau R, Vidaud M (2001) The CGA gene as new predictor of the response to endocrine therapy in ER a-positive postmenopausal breast cancer patients. Oncogene 20:6955–6959
Black R, White J (1998) ADAMs: focus on the protease domain. Curr Opin Cell Biol 10:654–659
Bolstad BM, Irizarry RA, Astrand M, Speed TP (2003) A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinformatics 19:185–193
Bunn P, Helfrich B, Brenner D, Chan D, Dykes D, Cohen A, Miller Y (1998) Effects of recombinant neutral endopeptidase (EC 3.4.24.11) on the growth of lung cancer cell lines in vitro and in vivo. Clin Cancer Res 4:2849–2858
Cairns R, Khokha R, Hill R (2003) Molecular mechanisms of tumor invasion and metastasis: an integrated view. Curr Mol Med 3:659–671
Chen Y, Layne M, Chung S, Ejima K, Baron R, Yet S, Perrella M (2003) Elk-3 is a transcriptional repressor of nitric-oxide synthase 2. J Biol Chem 278:39572–39577
Dittmer J, Nordheim A (1998) Ets transcription facotrs and human disease. BiochimBiophysActa 1377:F1–11
Drubin D, Smith JS, Liu W, Zhao W, Chase G, Clawson G (2005) Comparison of cryopreservation and standard needle biopsy for gene expression profiling of human breast cancer specimens. Breast Can Res Treat 90:93–96
Edmondson S, Thumiger S, Kaur P, Loh B, Loelmeyer R, Li A, Silha J, Murphy J, Werther G (2005) Insulin-like growth factor␣binding protein-3 (IGFBP-3) localiozes to and modulates epidermal keratinocytes in vivo. Br J Dermatol 152:225–230
Erin N, Boyer P, Bonneau R, Clawson G, Welch D (2004) Capsaicin-mediated denervation of sensory neurons promotes mammary tumor metastasis to lung and heart. Anticancer Res 24:1003–1009
Erin N, Clawson G (2004) Parameters affecting substance P measurement inheart, lung, and skin. BioTechiques 37:232–236
Erin N, Lehman R, Boyer P, Billingsley M (2003) In vitro hypoxia and excitotoxicity in human brain induces calcineurin-Bcl-2 interactions. Neuroscience 117:557–565
Fambrough D, Pan D, Rubin G, Goodman C (1996) The cell surface metalloprotease/disintegrin Kuzbanian is required for axonal extension in Drosophila. Proc Natl Acad Sci(USA) 93:13233–13238
Foos G, Garcia-Ramirez J, Galang C, Hauser C (1998) Elevated expression of Ets2 or distinct portions of Ets2 can reverse Ras-mediated cellular transformation. J Biol Chem 273:18871–18880
Friess H, Zhu Z, Liard V, Shi X, Shrikhande S, Wang L, Lieb K, Korc M, Palma C, Zimmermann A, Reubi J, Buchler M (2003) Neurokinin-1 receptor expression and its potential effects on tumor growth in human pancreatic cancer. Lab Invest 83:731–742
Granderath S, Stollewerk A, Greig S, Goodman C, O’Kane C, Klambt C (1999) Loco encodes an RGS protein required for Drosophila glial differentiation. Development 126:1781–1791
Hallberg M, Nyberg F (2003) Neuropeptide conversion to bioactive fragments –an important pathway in neuromodulation. Curr Protein Pept Sci 4:31–44
Hanafusa T, Shinji T, Shiranha H, Nouso K, Iwasaki Y, Yumoto J, Ono T, Koide N (2005) Functional promoter upstream p53 regulatory sequence of IGFBP3 that is silenced by specific methylation. BMC Cancer 5:9–15
Hanahan D, Weinberg R (2000) The hallmarks of cancer. Cell 100:57–70
Heasley L (2001) Autocrine and paracine signaling through neuropeptide receptors in human cancer. Oncogene 20:1563–1569
Hirano T (2002) The ABCs of SMC proteins: two-armed ATPases for chromosome condensation, col, and repair. Genes Develop 16:399–414
Ho W, Xie Z, Zhao Z, Exton J (2005) Tyrosine phosphorylation of phospholipase D1 by v-Src does not per se result in activation. Cell Signal 17:691–699
Holmgren L, O’Reilly M, Folkman J (1995) Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nature Med 1:149–153
Hornfeldt C, Sun X, Larson A. (1994) The NH2-terminus of substance P modulates NMDA-induced activity in the mouse spinal cord. J Neurosci 14:3364–3369
Ikeda T, Ikeda K, Sasaki K, Kawakami K, Takahara J (1999) The inv(11)(p15q22) chromosome translocationof therapy-related myelodysplasia results in NUP98-DDX10 and DDX10-NUP98 fusion transcripts. Int J Hematol 69:160–164
Irizarry R, Gautier L, Cope LM (2003) The analysis of Gene Expression Data: Methods and software. Springer-Verlag
Irizarry RA, Hobbs B, Collin F, Beazer-Barclay YD, Antonellis KJ, Scherf U, Speed TP (2003b) Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 4:249–264
Iwata N, Mizukami H, Shirotani K, Takaki Y, Muramatsu S, Lu B, Gerard N, Ozawa K, Saido T (2004) Presynapticlocalization of neprilysin contributes to efficient clearance of amyloid-beta peptide in mouse brain. J Neurosci 24:991–998
Jones D, Mattei M, Horsley D, Crowell I, Singh P (2001) The␣gene and pseudogenes of Cbx3/mHP1 gamma. DNA Seq 12:147–160
Katoh M, Katoh M (2004) Identification and characterization of human DIAPH3 gene in silico. Int J Mol Med 13:473–478
Korfali N, Ruchaud S, Loegering D, Bernard D, Dingwall C, Kaufmann S, Earnshaw W (2004) Caspase-7 gene disruption reveals an involvement of the enzyme during the early stages of apoptosis. J Biol Chem 279:1030–1039
Kruger A, Soeltl R, Sopov I, Kopitz C, Arlt M, Magdolen V, Harbeck N, Gansbacher B, Schmitt M (2001) Hydroxamate-type matrix metalloproteinase inhibitor batimastat promotes liver metastasis. Cancer Res 61:1272–1275
Kurokawa H, Nishio K, Fukumoto H, Tomonari A, Suzuki T, Saijo N (1999) Alteration of caspase-3 (CPP32/Yama/apopain) in wild-type MCF-7, breast cancer cells. Oncol Rpts 6:33–37
Laigaard J, Christiansen M, Frohlich C, Pedersen B, Ottesen B, Wewer U (2005) The level of ADAM12-S in maternal serum is an early first-trimester marker of fetal trisomy 18. Prenat Diagn 25:45–46
Lang K, Drell T, Lindecke A, Niggemann B, Kaltschmidt C, Zaenker K, Entschladen F (2004) Induction of a metastatogenic tumor cell type by neurotransmitters and its pharmacological inhibition by established drugs. Int J Cancer 112:231–238
Latil A, Bieche I, Chene L, Laurendeau I, Berthon P, Cussenot O, Vidaud M (2003) Gene expression profiling in clinically localized prostate cancer: a four-gene expression model predicts clinical behavior. Clin Cancer Res 9:5477–5485
Lelekakis M, Moseley J, Martin T, et al (1999) A novel orthotopic model of breast cancer metastasis to bone. Clin Exptl Metastasis 17:163–170
Lendeckel U, Kohl J, Arndt M, Carl-McGrath S, Donat H, Rocken C (2005) Increased expression of ADAM family members in human breast cancer and breast cancer cell lines. J Cancer Res Clin Oncol 131:42–48
Li C, Wong WH (2001) Model-based analysis of oligonucleotide arrays: expression index cmoputation and outlier detection. Proc Natl Acad Sci(USA) 98:31–36
Lippke J, Gu Y, Sarnecki C, Caron P, Su M (1996) Identification and characterization of CPP32/Mch2 homolog 1, a novel cysteine protease similar to CPP32. J Biol Chem 271:1825–1828
MacKinnon A, Waters C, Jodrell D, Haslett C, Sethi T (2001) Bombesin and substance P analogues differentially regulate G-protein coupling to the bombesin receptor. Direct evidence for biased agonism. J Biol Chem 276:28082–28091
Mangus D, Evans M, Jacobson A (2003) Poly(A)-binding proteins: multifunctional scaffolds for the post-transcriptional control of gene expression. Genome Biol 4:223 (Epub.)
Maskos K, Fernandez-Catalan C, Huber R, Bourenkov G, Bartunik H, Ellestad G, Reddy P, Wolfson M, Ruach C, Castner B, Davis R, Clarke H, Petersen M, Fitzner J, Cerretti D, March c, Paxton R, Balck R, Bode W (1998) Crystal structure of the catalytic domain of human tumor necrosis factor-alpha-converting enzyme. Proc Natl Acad Sci(USA) 95:3408–3412
Mazzocchi G, Malendowicz L, Ziolkowska A, Spinazzi R, Rebuffat P, Aragona F, Ferrazzi E, Parnigotto P, Nussdorfer G (2004) Adrneomedullin (AM) and AM receptor type 2 expression is up-regulated in prostate carcinomas (PC), and AM stimulates in vitro growth of a PC-derived cell line by enhancing proliferation and decreasing apoptosis rates. Int J Oncol 25:1781–1787
McCulloch D, Akl P, Samaratunga H, Herington A, Odorico D (2004) Expression of the disintegrin metalloprotease, ADAM-10,␣in prostate cancer and its regulation by dihydrotestosterone, insulin-like growth factor 1, and epidermal growth factor in the␣prostate cancer cell model LNCaP. Clin Cancer Res 10: 314–323
McCuskey R (2004) Anatomy of efferent hepatic nerves. Anat Rec A Discov Mol Cell Evol Biol 280A:821–826
Mentlein R (1999) Dipeptidyl-peptidase IV (CD26)–role in the inactivation of regulatory peptides. Regul Pept 85:9–24
Mizuguchi S, Ohno T, Hattori Y, Kamata K, Arai K, Saeki T, Saigenji K, Hayashi I, Kuribayashi Y, Majima M (2005) Calcitonin gene-related peptide released by capsaicin suppresses myoelectrical activity of gastric smooth muscle. J Gastroenterol Hepatol 20:611–618
Neznanov N, Man A, Yamamoto H, Hauser C, Cardiff R, Oshima R (1999) A single targeted Ets2 allele restricts development of mammary tumors in transgenic mice. Cancer Res 59:4242–4246
Nozaki M, Onishi Y, Kanno N, Ono Y, Fujimura Y (1996) Molecular cloning of Elk-3, a new member of the Ets family expressed during mouse embryognesis and analysis of its transcriptional repression activity. DNA Cell Biol 15:855–862
Offley S, Guo T, Wei t, Clark J, Vogel H, Lindsey D, Jacobs C, Yao W, Lane N, Kingery W (2005) Capsaicin-sensitive sensory neurons contribute to the maintenance of trabecular bone integrity. J Bone Miner Res 20:257–267
Oikawa T (2004) ETS transcription factors: possible tragets for cancer therapy. Cancer Sci 95:626–633
Pai J, Brown M, Goldstein J (1996) Purification and cDNA cloning of a second apoptosis-related cysteine protease that cleaves and activates sterol regulatory element binding proteins. Proc Natl Acad Sci(USA) 93:5437–5442
Palma C, Bigioni M, Irrissuto C, Nardelli F, Maggi C, Manzini S (2000) Anti-tumor activity of tachykinin NK1 receptor antagonists on human glioma U373 MG xenografts. Br J Cancer 82:480–487
Palmerini F, Devilard E, Jarry A, Birg F, Xerri L (2001) Caspase 7 downregulation as an immunohistochemical marker of colonic carcinoma. Hum Pathol 32:461–467
Park S, Wu C, Safa A (2004) A P-glycoprotein- and MRP1-independent doxorubicin-resistant variant of the MCF-7 breast cancer cell line with defects in caspase-6, -7, and -10 activation pathways. Anticancer Res 24:123–131
Patois RVP, Cretin B (2000) Near field acoustic densimeter and viscosimeter. Rev Sci Instrum 71:3860
Perez M, Rompato G, Corbi N, DeGregorio L, Dragani T, Passananti C (1996) Zpf60, a mouse zinc finger gene expressed transiently during in vitro muscle differentiation. FEBS Lett 387:117–121
Postina R, Schroeder A, Dewachter I, Bohl J, Schmitt U, Kojro E, Prinzen C, Endres K, Hiemke C, Blessing M, Flamez P, Dequenne A, Godeau E, van Leuven F, Fahrenholz F (2004) A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model. J Clin Invest 113:1456–1464
Reed J (2000) Mechanisms of apoptosis. Am J Pathol 157:1415–1430
Rooke J, Pan D, Xu T, Rubin G (1996) KUZ, a conserved metalloprotease-disintegrin protein with two roles in Drosophila neurogenesis. Science 273:1227–1231
Rosati R, Adil M, Ali M, Eliason J, Orosz A, Sebestyen F, Kalemkerian G (1998) Induction of apoptosis by a short-chain neuropeptide analog in small cell lung cancer. Peptides 19:1519–1523
Sakurada C, Watanabe C, Sakurada T (2004) Occurrence of substance P(1–7) in the metabolism of substance P and its antinociceptive activity at the mouse spinal cord level. Meth Exp Clin Pharmacol 26:171–176
Sapi E, Flick M, Rodov S, Kacinski B (1998) Ets-2 transdominant mutant abolishes anchorage=independent growth and macrophage colony-stimulating factor-stimulated invasion by BT20 breast carcinoma cells. Cancer Res 58:1027–1033
Saria A, Skofitsch G, Lembeck F (1982) Distribution of capsaicin in rat tissues after systemic administration. J. Pharm Pharmacol 34:273–275
Savitsky K, Ziv Y, Bar-Shira A, LGilad S, Tagle D, Smith S, ‘Uziel T, Sfez S, Nahmias J, Sartiel A, Eddy R, Shows T, Rotman G (1996) A human gene (DDX10) encoding a putative DEAD-box RNA helicase at 11q22-q23. Genomics 33:199–206
Schlondorff J, Blobel C (1999) Metalloprotease-disintegrins: modular proteins capable of promoting cell-cell interactions and triggering signals by protein-ectodomain shedding. J Cell Sci 112(pt. 21):3603–3617
Seki Y, Suico M, Uto A, Hisatsure A, Shuto T, Isohama Y, Kai H (2002) The ETS transcription factor MEF is a candidate tumor suppressor gene on the X chromosome. Cancer Res 62:6579–6586
Session D, Lee G, Wolgemuth D (2001) Charactrerization of D1Pas1, a mouse autosomal homologue of the human AZFa represents a nuclear protein in spermatogenic cells. Fertil Steril 76:804–811
Shin M, Kim H, Lee S, Lee J, Song Y, Kim Y, Park W, Kim S, Lee S, Park J, Lee J, Xiao W, Jo K, Wang Y, Lee K, Park Y, Kim S, Lee J, Yoo N (2002) Alterations of Fas-pathway genes associated with nodal metastasis in non-small cell lung cancer. Oncogene 21:4129–4136
Shindoh M, Higashino F, Kohgo T (2004) E1AF, an ets-oncogene family transcription factor. Cancer Lett 216:1–8
Singh D, Joshi D, Hameed M, Qian J, Gascon P, Maloof P, Mosenthal A, Rameshwar P (2000) Increased expression of preprotachykinin-I and neurokinin receptors in human breast cancer cells: implications for bone marrow metastasis. Proc Natl Acad Sci(USA) 97:388–393
Skidgel R, Engelbrecht S, Johnson A, et al (1984) Hydrolysis of substance P and neurotensin by converting enzyme and neutral endopeptidase. Peptides 5:769
Skidgel R, Erdos E (2004) Angiotensin converting enzyme (ACE) and neprilysin hydrolyze neuropeptides: a brief history, the beginning and follow-ups to early studies. Peptides 25:521–525
Slee E, Harte M, Kluck R, Wolf B, Casiano C, Newmeyer D, Wang H, Reed J, Nicholson D, Alnemri E, Green D, Martin S (1999) Ordering the cytochrome c-initiated caspase cascade: hierarchical activation of caspases-2, -3, -6, -7, -8, and -10 in a caspase-9 dependent manner. J Cell Biol 144:281–292
Soung Y, Lee J, Kim H, Park W, Kim S, Lee J, Park J, Cho Y, Kim C, Park Y, Nam S, Jeong S, Kim S, Lee J, Yoo N, Lee S (2003) Inactivating mutations of CASPASE-7 gene in human cancers. Oncogene 22:8048–8052
Steele V, Hawk E, Viner J, Lubet R (2003) Mechanisms and applications of non-steroidal anti-inflammatory drugs in the cheomprevention of cancer. Mutat Res 523–524:137–144
Takasu M, Tada Y, Wang J, Tagawa M, Takenaga K (1999) Resistance to apoptosis induced by microenvironmental srtresses is correlated with metastatic potential in Lewis lung carcinoma. Clin Exp Metastasis 17:409–416
Tatenhorst L, Senner V, Puttmann S, Paulus W (2004) Regulators of G-protein signaling 3 and 4 (RGS3, RGS4) are associated with glioma invasion and motility. Neuropathol Exp Neurol 63:210–222
Taylor E, Moghraby J, Lees J, Smit B, Moens P, Lehmann A (2001) Characterization of a novel human SMC heterodimer homologous to the S. pombe Rad18/Spr18 complex. Mol Biol Cell 12:1583–1594
Tokuhara T, Adachi M, Hashida H, Ishida H, Taki T, Higashiyama M, Kodama K, Tachibana S, Sasaki S, Miyake M (2001) Neutral endopeptidase/CD10 and aminopeptidase N/CD13 gene expression as a prognostic factor in non-small cell lung cancer. Jpn J Thorac Cardiovasc Surg 49:489–496
Tusher VG, Tibshirani R, Chu G (2001) Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci(USA) 98:5116–5121
Walsh D, Hu d, Mapp P, Polak J, Blake D, Fan T (1996) Innervation and neurokinin receptors during angiogenesis in the rat sponge granuloma. Histochemical J 28:759–769
Wasylyk B, Hahn S, Giovane A (1993) The Ets family of transcription factors. Eur J Biochem 211:7–18
Wesley U, Albino A, Tiwari S, Houghton A (1999) A role for dipeptidyl peptidase IV in suppressing the malignant phenotype of melaoncytic cells. J Exp Med 190:311–322
Wilczak N, Ramsaransing g, Mostert J, Chesik D, De Keyser J (2005) Serum levels of insulin-like growth factor-1 and insulin-like growth factor binding protein 3 in relapsing and primary progressive multiple sclerosis. Mult Schler 11:13–15
Yamamoto M, Kakihana K, Kurosu T, Murakami N, Miura O (2005) Clonal evolution with inv(11)(p15q22) and NUP98/DDX10 fusion gene in imatinib-resistant chronic myelogenous leukemia. Cancer Genet Cytogenet 157:104–108
Yoon M, Yon C, Park S, Oh D, Han A, Kim D, Han J (2005) Role of phospholipaseD1 in neurite outgrowth in neural stem cells. Biochem Biophys Res Commun 329:804–811
Yu A, Hewitt R, Connor E, Stetler-Stevenson W (1997) Matrix metalloproteinases. NOvel targets for directed cancer therapy. Drugs Aging 11:229–244
Yukhananov R, Larson A (1994) An N-terminal fragment of substance P, substance P(1–7), down-regulates neurokinin-1 binding in the mouse spinal cord. Neurosci Lett 178:163–166
Zheng T, Hunot S, Kuida K, Flavell R (1999) Caspase knockouts: matters of life and death. Cell Death Differ 6:1043–1053
Acknowledgements
This work was supported by funds from the Gittlen Cancer Research Foundation, and by funds from the Pennsylvania Department of Health (which specifically disclaims responsibility for analyses, interpretations, or conclusions), and by Akdeniz University Research Units, Antalya, Turkey.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Erin, N., Zhao, W., Bylander, J. et al. Capsaicin-induced inactivation of sensory neurons promotes a more aggressive gene expression phenotype in breast cancer cells. Breast Cancer Res Treat 99, 351–364 (2006). https://doi.org/10.1007/s10549-006-9219-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10549-006-9219-7