Triple-negative breast cancer: New therapeutic options via signalling transduction cascades

Andergassen,Ulrich; Kölbl,Alexandra  C.; Mumm,Jan-Niclas; Mahner,Sven; Jeschke,Udo

doi:10.3892/or.2017.5512

Triple-negative breast cancer: New therapeutic options via signalling transduction cascades

Authors:
- Ulrich Andergassen
- Alexandra C. Kölbl
- Jan-Niclas Mumm
- Sven Mahner
- Udo Jeschke
View Affiliations

Affiliations: Department of Obstetrics and Gynaecology, Ludwig-Maximilians University of Munich, 80337 Munich, Germany
Published online on: March 16, 2017 https://doi.org/10.3892/or.2017.5512
Pages: 3055-3060

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Triple-negative breast cancer is a highly aggressive type of mammalian carcinoma. It is defined by a rather weak expression of estrogen-, progesterone- and Her2-receptor, and is thus difficult to treat, resulting in low disease-free and overall survival rates of the affected patients. Hence it is important to find new therapeutic options. To this aim we analysed the incidence of some molecules from different signal transduction cascades by immunohistochemistry, which are known to correlate with triple-negative breast cancer, and correlated the expression of these molecules to different tumour traits, such as size, grading, menopausal stage, histology, lymph node affection, remote metastasis formation, and to the incidence of local and lymph node recurrence and metastasis by statistical analysis. Statistically significant correlations were found for a number of tumour characteristics and signalling molecules: HIF1α is correlated to tumour grading, β-catenin to the menopausal state of the patient, and for Notch1 a relation to lymph node affection is seen. In terms of different recurrences, a correlation of β-catenin to metastasis formation and lymph node affection could be shown, as well as coherences between XBP1 and lymph node recurrence, Notch1 and metastasis formation and FOXP3 and the occurrence of local recurrence. The presented results are in accordance with formerly published studies and therefore might comprise opportunities to develop new therapeutical strategies, which could help to handle this aggressive form of breast cancer in a manner, by which side effects would be reduced and therapeutical efficiency is increased.

View Figures

View References

1	Robert Koch Institut: Krebs in Deutschland 2011/2012. 10th. Berlin: 2015, (In German). http://www.gekid.de/Doc/krebs_in_deutschland_2015.pdf
2	National Cancer Institute. simplewww.cancer.govNIHAccessed. Nov;2015.
3	Badve S, Dabbs DJ, Schnitt SJ, Baehner FL, Decker T, Eusebi V, Fox SB, Ichihara S, Jacquemier J, Lakhani SR, et al: Basal-like and triple-negative breast cancers: A critical review with an emphasis on the implications for pathologists and oncologists. Mod Pathol. 24:157–167. 2011. View Article : Google Scholar : PubMed/NCBI
4	Brenton JD, Carey LA, Ahmed AA and Caldas C: Molecular classification and molecular forecasting of breast cancer: Ready for clinical application? J Clin Oncol. 23:7350–7360. 2005. View Article : Google Scholar : PubMed/NCBI
5	Dawood S: Triple-negative breast cancer: Epidemiology and management options. Drugs. 70:2247–2258. 2010. View Article : Google Scholar : PubMed/NCBI
6	Kennecke H, Yerushalmi R, Woods R, Cheang MC, Voduc D, Speers CH, Nielsen TO and Gelmon K: Metastatic behavior of breast cancer subtypes. J Clin Oncol. 28:3271–3277. 2010. View Article : Google Scholar : PubMed/NCBI
7	Hugh J, Hanson J, Cheang MC, Nielsen TO, Perou CM, Dumontet C, Reed J, Krajewska M, Treilleux I, Rupin M, et al: Breast cancer subtypes and response to docetaxel in node-positive breast cancer: Use of an immunohistochemical definition in the BCIRG 001 trial. J Clin Oncol. 27:1168–1176. 2009. View Article : Google Scholar : PubMed/NCBI
8	Mehta RS: Dose-dense and/or metronomic schedules of specific chemotherapies consolidate the chemosensitivity of triple-negative breast cancer: A step toward reversing triple-negative paradox. J Clin Oncol. 26:3286–3288. 2008. View Article : Google Scholar : PubMed/NCBI
9	Liedtke C, Mazouni C, Hess KR, André F, Tordai A, Mejia JA, Symmans WF, Gonzalez-Angulo AM, Hennessy B, Green M, et al: Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol. 26:1275–1281. 2008. View Article : Google Scholar : PubMed/NCBI
10	O'Shaughnessy J, Osborne C, Pippen JE, Yoffe M, Patt D, Rocha C, Koo IC, Sherman BM and Bradley C: Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med. 364:205–214. 2011. View Article : Google Scholar : PubMed/NCBI
11	Linderholm BK, Hellborg H, Johansson U, Elmberger G, Skoog L, Lehtiö J and Lewensohn R: Significantly higher levels of vascular endothelial growth factor (VEGF) and shorter survival times for patients with primary operable triple-negative breast cancer. Ann Oncol. 20:1639–1646. 2009. View Article : Google Scholar : PubMed/NCBI
12	Schutz FA, Jardim DL, Je Y and Choueiri TK: Haematologic toxicities associated with the addition of bevacizumab in cancer patients. Eur J Cancer. 47:1161–1174. 2011. View Article : Google Scholar : PubMed/NCBI
13	von Minckwitz G, Eidtmann H, Rezai M, Fasching PA, Tesch H, Eggemann H, Schrader I, Kittel K, Hanusch C, Kreienberg R, et al: German Breast Group; Arbeitsgemeinschaft Gynäkologische Onkologie-Breast Study Groups: Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer. N Engl J Med. 366:299–309. 2012. View Article : Google Scholar : PubMed/NCBI
14	Grob TJ, Heilenkötter U, Geist S, Paluchowski P, Wilke C, Jaenicke F, Quaas A, Wilczak W, Choschzick M, Sauter G, et al: Rare oncogenic mutations of predictive markers for targeted therapy in triple-negative breast cancer. Breast Cancer Res Treat. 134:561–567. 2012. View Article : Google Scholar : PubMed/NCBI
15	Viale G, Rotmensz N, Maisonneuve P, Bottiglieri L, Montagna E, Luini A, Veronesi P, Intra M, Torrisi R, Cardillo A, et al: Invasive ductal carcinoma of the breast with the ‘triple-negative’ phenotype: Prognostic implications of EGFR immunoreactivity. Breast Cancer Res Treat. 116:317–328. 2009. View Article : Google Scholar : PubMed/NCBI
16	Baselga J, Stemmer S, Pego A, Chan A, Goeminne JC, Graas MP, Kennedy J, Gil Ciruelos EM, Zubel A, et al: Abstract PD01-01: Cetuximab + cisplatin in estrogen receptor-negative, progesterone receptor-negative, Her2-negative (triple-negative) metastatic breast cancer: Results of the randomized phase II BALI-trial. Cancer Res (Thirty-Third Annual CTRC-AACR San Antonio Breast Cancer Symposium). 70:PD01–01. 2010.
17	Yunokawa M, Koizumi F, Kitamura Y, Katanasaka Y, Okamoto N, Kodaira M, Yonemori K, Shimizu C, Ando M, Masutomi K, et al: Efficacy of everolimus, a novel mTOR inhibitor, against basal-like triple-negative breast cancer cells. Cancer Sci. 103:1665–1671. 2012. View Article : Google Scholar : PubMed/NCBI
18	Qiu M, Peng Q, Jiang I, Carroll C, Han G, Rymer I, Lippincott J, Zachwieja J, Gajiwala K, Kraynov E, et al: Specific inhibition of Notch1 signaling enhances the antitumor efficacy of chemotherapy in triple negative breast cancer through reduction of cancer stem cells. Cancer Lett. 328:261–270. 2013. View Article : Google Scholar : PubMed/NCBI
19	Zhu H, Bhaijee F, Ishaq N, Pepper DJ, Backus K, Brown AS, Zhou X and Miele L: Correlation of Notch1, pAKT and nuclear NF-κB expression in triple negative breast cancer. Am J Cancer Res. 3:230–239. 2013.PubMed/NCBI
20	Schwab LP, Peacock DL, Majumdar D, Ingels JF, Jensen LC, Smith KD, Cushing RC and Seagroves TN: Hypoxia-inducible factor 1α promotes primary tumor growth and tumor-initiating cell activity in breast cancer. Breast Cancer Res. 14:R62012. View Article : Google Scholar : PubMed/NCBI
21	Chen X, Iliopoulos D, Zhang Q, Tang Q, Greenblatt MB, Hatziapostolou M, Lim E, Tam WL, Ni M, Chen Y, et al: XBP1 promotes triple-negative breast cancer by controlling the HIF1α pathway. Nature. 508:103–107. 2014. View Article : Google Scholar : PubMed/NCBI
22	Lopes LF, Guembarovski RL, Guembarovski AL, Kishima MO, Campos CZ, Oda JM, Ariza CB, de Oliveira KB, Borelli SD and Watanabe MA: FOXP3 transcription factor: A candidate marker for susceptibility and prognosis in triple negative breast cancer. Biomed Res Int. 2014:3416542014.PubMed/NCBI
23	Takenaka M, Seki N, Toh U, Hattori S, Kawahara A, Yamaguchi T, Koura K, Takahashi R, Otsuka H, Takahashi H, et al: FOXP3 expression in tumor cells and tumor-infiltrating lymphocytes is associated with breast cancer prognosis. Mol Clin Oncol. 1:625–632. 2013.PubMed/NCBI
24	Kim W, Kim SY, Kim T, Kim M, Bae DJ, Choi HI, Kim IS and Jho E: ADP-ribosylation factors 1 and 6 regulate Wnt/β-catenin signaling via control of LRP6 phosphorylation. Oncogene. 32:3390–3396. 2013. View Article : Google Scholar : PubMed/NCBI
25	Mahamodhossen YA, Liu W and Rong-Rong Z: Triple-negative breast cancer: New perspectives for novel therapies. Med Oncol. 30:6532013. View Article : Google Scholar : PubMed/NCBI
26	Yang L, Perez AA, Fujie S, Warden C, Li J, Wang Y, Yung B, Chen YR, Liu X, Zhang H, et al: Wnt modulates MCL1 to control cell survival in triple negative breast cancer. BMC Cancer. 14:1242014. View Article : Google Scholar : PubMed/NCBI
27	Remmele W and Stegner HE: Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Pathologe. 8:138–140. 1987.PubMed/NCBI
28	Jin Y, Wang H, Liang X, Ma J and Wang Y: Pathological and prognostic significance of hypoxia-inducible factor 1α expression in epithelial ovarian cancer: A meta-analysis. Tumour Biol. 35:8149–8159. 2014. View Article : Google Scholar : PubMed/NCBI
29	Wang Y, Liu Y, Ma JX, Li BX and Li YK: Effect of the Wnt/LRP5/β-catenin signaling pathway on the pathogenesis of postmenopausal osteoporosis. Zhonghua Fu Chan Ke Za Zhi. 46:769–772. 2011.(In Chinese). PubMed/NCBI
30	Yin L, Gao Y, Zhang X, Wang J, Ding D, Zhang Y, Zhang J and Chen H: Niclosamide sensitizes triple-negative breast cancer cells to ionizing radiation in association with the inhibition of Wnt/β-catenin signaling. Oncotarget. 7:42126–42138. 2016.PubMed/NCBI
31	Rangel MC, Bertolette D, Castro NP, Klauzinska M, Cuttitta F and Salomon DS: Developmental signaling pathways regulating mammary stem cells and contributing to the etiology of triple-negative breast cancer. Breast Cancer Res Treat. 156:211–226. 2016. View Article : Google Scholar : PubMed/NCBI
32	Cao YW, Wan GX, Sun JP, Cui XB, Hu JM, Liang WH, Zheng YQ, Li WQ and Li F: Implications of the Notch1-Snail/Slug-epithelial to mesenchymal transition axis for lymph node metastasis in infiltrating ductal carcinoma. Kaohsiung J Med Sci. 31:70–76. 2015. View Article : Google Scholar : PubMed/NCBI
33	Cao YW, Li WQ, Wan GX, Li YX, Du XM, Li YC and Li F: Correlation and prognostic value of SIRT1 and Notch1 signaling in breast cancer. J Exp Clin Cancer Res. 33:972014. View Article : Google Scholar : PubMed/NCBI
34	Mohammadi-Yeganeh S, Mansouri A and Paryan M: Targeting of miR9/NOTCH1 interaction reduces metastatic behavior in triple-negative breast cancer. Chem Biol Drug Des. 86:1185–1191. 2015. View Article : Google Scholar : PubMed/NCBI
35	Pamarthy S, Mao L, Katara GK, Fleetwood S, Kulshreshta A, Gilman-Sachs A and Beaman KD: The V-ATPase a2 isoform controls mammary gland development through Notch and TGF-β signaling. Cell Death Dis. 7:e24432016. View Article : Google Scholar : PubMed/NCBI
36	Lee KM, Nam K, Oh S, Lim J, Kim RK, Shim D, Choi JH, Lee SJ, Yu JH, Lee JW, et al: ECM1 regulates tumor metastasis and CSC-like property through stabilization of β-catenin. Oncogene. 34:6055–6065. 2015. View Article : Google Scholar : PubMed/NCBI
37	Kumar KJ, Vani MG, Chueh PJ, Mau JL and Wang SY: Antrodin C inhibits epithelial-to-mesenchymal transition and metastasis of breast cancer cells via suppression of Smad2/3 and β-catenin signaling pathways. PLoS One. 10:e01171112015. View Article : Google Scholar : PubMed/NCBI
38	Li X, Liang W, Liu J, Lin C, Wu S, Song L and Yuan Z: Transducin (β)-like 1 X-linked receptor 1 promotes proliferation and tumorigenicity in human breast cancer via activation of beta-catenin signaling. Breast Cancer Res. 16:4652014. View Article : Google Scholar : PubMed/NCBI
39	Wang Y, Bu F, Royer C, Serres S, Larkin JR, Soto MS, Sibson NR, Salter V, Fritzsche F, Turnquist C, et al: ASPP2 controls epithelial plasticity and inhibits metastasis through β-catenin-dependent regulation of ZEB1. Nat Cell Biol. 16:1092–1104. 2014. View Article : Google Scholar : PubMed/NCBI
40	Sehgal P, Kumar N, Kumar Praveen VR, Patil S, Bhattacharya A, Vijaya Kumar M, Mukherjee G and Kondaiah P: Regulation of protumorigenic pathways by insulin like growth factor binding protein2 and its association along with β-catenin in breast cancer lymph node metastasis. Mol Cancer. 12:632013. View Article : Google Scholar : PubMed/NCBI
41	Dong Y, Zhang T, Li J, Deng H, Song Y, Zhai D, Peng Y, Lu X, Liu M, Zhao Y, et al: Oridonin inhibits tumor growth and metastasis through anti-angiogenesis by blocking the Notch signaling. PLoS One. 9:e1138302014. View Article : Google Scholar : PubMed/NCBI