Breast cancer had been the first non-hematologic malignancy where sub-types based on molecular characterization had entered clinical practice. HER2 over-expression, due to either gene amplification or protein up-regulation, defines one of these sub-types and is clinically exploited by addition of HER2-targeted treatments to the regimens of treatment. Nevertheless, in many occasions HER2-positive cancers are resistant or become refractory to these therapies. Several mechanisms, such as activation of alternative pathways or loss of expression of the receptor in cancer cells, have been proposed as the cause of these therapeutic failures. Cancer stem cells (CSCs, alternatively called tumor-initiating cells) comprise a small percentage of the tumor cells, but are capable of reconstituting and propagating tumors due to their superior intrinsic capacity for regeneration, survival and resistance to therapies. CSCs possess circuits enabling epigenetic plasticity which endow them with the ability to alternate between epithelial and mesenchymal states. This paper will discuss the expression and regulation of HER2 in CSCs of the different sub-types of breast cancer and relationships of the receptor with both the circuits of stemness and epithelial–mesenchymal plasticity. Therapeutic repercussions of the relationship of HER2-initiated signaling with stemness networks will also be proposed.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Ahmed S, Sami A, Xiang J. HER2-directed therapy: current treatment options for HER2-positive breast cancer. Breast Cancer. 2015;22:101–16.
Prat A, Pineda E, Adamo B, Galván P, Fernádez A, Gaba L, et al. Clinical implications of the intrinsic subtypes of breast cancer. Breast. 2015;24:S26–35.
Chaffer CL, Brueckmann I, Scheel C, Kaestli AJ, Wiggins PA, Rodrigues LO, et al. Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state. Proc Natl Acad Sci. 2011;108:7950–5.
Ferrari A, Vincent-Salomon A, Pivot X, Sertier AS, Thomas E, Tonon L, et al. A whole-genome sequence and transcriptome perspective on HER2-positive breast cancers. Nat Commun. 2016;7:12222.
Sørlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA. 2001;98:10869–74.
Korkaya H, Wicha MS. HER2 and breast cancer stem cells: more than meets the eye. Cancer Res. 2013;73:3489–93.
Paik S, Kim C, Wolmark N. HER2 status and benefit from adjuvant trastuzumab in breast cancer. N Engl J Med. 2008;358:1409–11.
Fehrenbacher L, Cecchini RS, Geyer CE, Rastogi P, Costantino JP, Atkins JN et al. NSABP B-47 (NRG oncology): Phase III randomized trial comparing adjuvant chemotherapy with adriamycin (A) and cyclophosphamide (C) → weekly paclitaxel (WP), or docetaxel (T) and C with or without a year of trastuzumab (H) in women with node-positive or high-risk node-negative invasive breast cancer (IBC) expressing HER2 staining intensity of IHC 1+ or 2+ with negative FISH (HER2-Low IBC). Cancer Res. 2018;78(4 Suppl):Abstract nr GS1-02.
Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, et al. The epithelial–mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133:704–15.
Morel AP, Lièvre M, Thomas C, Hinkal G, Ansieau S, Puisieux A. Generation of breast cancer stem cells through epithelial–mesenchymal transition. PLoS One. 2008;3:e2888.
Voutsadakis IA. The network of pluripotency, epithelial mesenchymal transition and prognosis of breast cancer. Breast Cancer Targets Therap. 2015;7:303–19.
Arteaga CL, Engelman JA. ERBB receptors: from oncogene discovery to basic science to mechanism-based cancer therapeutics. Cancer Cell. 2014;25:282–303.
Nami B, Wang Z. HER2 in breast cancer stemness: A negative feedback loop towards trastuzumab resistance. Cancer. 2017;9:40.
Meng F, Speyer CL, Zhang B, Zhao Y, Chen W, Gorski DH, et al. PDGFRα and β play critical roles in mediating Foxq1-driven breast cancer stemness and chemoresistance. Cancer Res. 2015;75:584–93.
Nozaki Y, Tamori S, Inada M, Katayama R, Nakane H, Minamishima O, et al. Correlation between c-Met and ALDH1 contributes to the survival and tumor-sphere formation of ALDH1 positive breast cancer stem cells and predicts poor clinical outcome in breast cancer. Gene Cancer. 2017;8:628–39.
Zhao D, Mo Y, Li MT, Li MT, Zou SW, Cheng ZL, et al. NOTCH-induced aldehyde dehydrogenase 1A1 deacetylation promotes breast cancer stem cells. J Clin Invest. 2014;124:5453–65.
Lamb R, Ablett MP, Spence K, Landberg G, Sims AH, Clarke RB. Wnt pathway activity in breast cancer sub-types and stem-like cells. PLoS One. 2013;8:e67811.
Tanaka H, Nakamura M, Kameda C, Kubo M, Sato N, Kuroki S, et al. The Hedgehog pathway plays an essential role in maintaining the CD44+CD24−/low subpopulation and the side population of breast cancer cells. Anticancer Res. 2009;29:2147–57.
Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131:861–72.
Voutsadakis IA. The ubiquitin-proteasome system and signal transduction pathways regulating epithelial mesenchymal transition of cancer. J Biomed Sci. 2012;19:67.
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.
Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2009;365:1273–83.
Duru N, Fan M, Candas D, Menaa C, Liu HC, Nantajit D, et al. HER2-associated radioresistance of breast cancer stem cells isolated from HER2 negative breast cancer cells. Clin Cancer Res. 2012;18:6634–47.
Oliveras-Ferraros C, Vazquez-Martin A, Martin-Castillo B, Cufí S, Del Barco S, Lopez-Bonet E, et al. Dynamic emergence of the mesenchymal CD44posCD24neg/low phenotype in HER2-gene amplified breast cancer cells with de novo resistance to trastuzumab (Herceptin). Biochem Biophys Res Commun. 2010;397:27–33.
Korkaya H, Paulson A, Iovino F, Wicha MS. HER2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion. Oncogene. 2008;27:6120–30.
Baker AT, Zlobin A, Osipo C. Notch-EGFR/HER2 bidirectional crosstalk in breast cancer. Front Oncol. 2014;4:1–15.
Harrison H, Simões BM, Rogerson L, Howell SJ, Landberg G, Clarke RB. Oestrogen increases the activity of oestrogen receptor negative breast cancer stem cells through paracrine EGFR and Notch signalling. Breast Cancer Res. 2013;15:R21.
Chen Y, Fischer WH, Gill GN. Regulation of the ERBB2 promoter by RBPJκ and NOTCH. J Biol Chem. 1997;272:14110–4.
Ju JH, Yang W, Oh S, Nam K, Lee KM, Noh DY, et al. HER2 stabilizes survivin while concomitantly down-regulating survivin gene transcription by suppressing Notch cleavage. Biochem J. 2013;451:123–34.
Magnifico A, Albano L, Campaner S, Delia D, Castiglioni F, Gasparini P, et al. Tumor-initiating cells of HER2-positive carcinoma cell lines express the highest oncoprotein levels and are sensitive to trastuzumab. Clin Cancer Res. 2009;15:2010–21.
Timmerman LA, Grego-Bessa J, Raya A, Bertrán E, Pérez-Pomares JM, Díez J, et al. Notch promotes epithelial–mesenchymal transition during cardiac development and oncogenic transformation. Gene Dev. 2004;18:99–115.
Leong KG, Niessen K, Kulic I, Raouf A, Eaves C, Pollet I, et al. Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin. J Exp Med. 2007;204:2935–48.
Shao S, Zhao X, Zhang X, Luo M, Zuo X, Huang S, et al. Notch1 signaling regulates the epithelial–mesenchymal transition and invasion of breast cancer in a Slug-dependent manner. Mol Cancer. 2015;14:1–17.
Osipo C, Patel P, Rizzo P, Clementz AG, Hao L, Golde TE, et al. ErbB-2 inhibition activates Notch-1 and sensitizes breast cancer cells to a gamma-secretase inhibitor. Oncogene. 2008;27:5019–32.
Abravanel DL, Belka GK, Pan TC, Pant DK, Collins MA, Sterner CJ, et al. Notch promotes recurrence of dormant tumor cells following HER2/neu-targeted therapy. J Clin Invest. 2015;125:2484–96.
Voutsadakis IA. Pathogenesis of colorectal carcinoma and therapeutic implications: the roles of the ubiquitin-proteasome system and Cox-2. J Cell Mol Med. 2007;11:252–85.
Pap M, Cooper GM. Role of glycogen synthase kinas-3 in the phosphatidylinositol 3-kinase/Akt cell survival pathway. J Biol Chem. 1998;273:19929–32.
Dey N, Young B, Abramovitz M, Bouzyk M, Barwick B, De P, et al. Differential activation of Wnt-β-catenin pathway in triple negative breast cancer increases MMP7 in a PTEN dependent manner. PLoS One. 2013;8:1–17.
Wu Y, Tran T, Dwabe S, Sarkissyan M, Kim J, Nava M, et al. A83-01 inhibits TGF-β-induced upregulation of Wnt3 and epithelial to mesenchymal transition in HER2-overexpressing breast cancer cells. Br Cancer Res Treat. 2017;163:449–60.
Liu X, Fridman JS, Wang Q, Caulder E, Yang G, Covington M, et al. Selective inhibition of ADAM metalloproteases blocks HER-2 extracellular domain (ECD) cleavage and potentiates the anti-tumor effects of trastuzumab. Cancer Biol Ther. 2006;5:648–56.
Wu Y, Ginther C, Kim J, Mosher N, Chung S, Slamon D, et al. Expression of Wnt3 activates Wnt/-catenin pathway and promotes EMT-like phenotype in trastuzumab-resistant HER2-overexpressing breast cancer cells. Mol Cancer Res. 2012;10:1597–606.
Martínez-Revollar G, Garay E, Martin-Tapia D, Nava P, Huerta M, Lopez-Bayghen E, et al. Heterogeneity between triple negative breast cancer cells due to differential activation of Wnt and PI3K/AKT pathways. Exp Cell Res. 2015;339:67–80.
O’Brien NA, McDonald K, Tong L, von Euw E, Kalous O, Conklin D, et al. Targeting PI3K/mTOR overcomes resistance to HER2-targeted therapy independent of feedback activation of AKT. Clin Cancer Res. 2014;20:3507–20.
Creedon H, Gómez-Cuadrado L, Tarnauskaite Z, Balla J, Canel M, MacLeod KG, et al. Identification of novel pathways linking epithelial-to-mesenchymal transition with resistance to HER2-targeted therapy. Oncotarget. 2016;7:11539–52.
Singh JK, Farnie G, Bundred NJ, Simões BM, Shergill A, Landberg G, et al. Targeting CXCR1/2 significantly reduces breast cancer stem cell activity and increases the efficacy of inhibiting HER2 via HER2-dependent and -independent mechanisms. Clin Cancer Res. 2013;19:643–56.
Aceto N, Duss S, Macdonald G, Meyer DS, Roloff TC, Hynes NE, et al. Co-expression of HER2 and HER3 receptor tyrosine kinases enhances invasion of breast cancer cells via stimulation of interleukin-8 autocrine secretion. Breast Cancer Res. 2012;14:R131.
Korkaya H, Wicha MS. Breast cancer stem cells: we’ve got them surrounded. Clin Cancer Res. 2013;19:511–3.
Iliopoulos D, Hirsch HA, Struhl K. An Epigenetic switch involving NF-κB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation. Cell. 2009;139:693–706.
Feng C, Neumeister V, Ma W, Xu J, Lu L, Bordeaux J, et al. Lin28 regulates HER2 and promotes malignancy through multiple mechanisms. Cell Cycle. 2012;11:2486–94.
Liu D, Deng Q, Sun L, Wang T, Yang Z, Chen H, et al. A Her2-let-7-β2-AR circuit affects prognosis in patients with Her2-positive breast cancer. BMC Cancer. 2015;15:1–10.
Kim J, Kim H, Seong M, Seol H, Oh JS. STAT3-survivin signaling mediates a poor response to radiotherapy in HER2-positive breast cancers. Oncotarget. 2016;7:1–11.
Chung SS, Giehl N, Wu Y, Vadgama JV. STAT3 activation in HER2-overexpressing breast cancer promotes epithelial–mesenchymal transition and cancer stem cell traits. Int J Oncol. 2014;44:403–11.
Qian L, Chen L, Shi M, Yu M, Jin B, Hu M, et al. A novel cis-acting element in Her2 promoter regulated by Stat3 in mammary cancer cells. Biochem Biophys Res Commun. 2006;345:660–8.
Huang WC, Hung CM, Wei CT, Chen TM, Chien PH, Pan HL, et al. Interleukin-6 expression contributes to lapatinib resistance through maintenance of stemness property in HER2-positive breast cancer cells. Oncotarget. 2016;7:62352–63.
Bharti R, Dey G, Mandal M. Cancer development, chemoresistance, epithelial to mesenchymal transition and stem cells: a snapshot of IL-6 mediated involvement. Cancer Lett. 2016;375:51–61.
Kim SY, Kang JW, Song X, Kim BK, Yoo YD, Kwon YT, et al. Role of the IL-6-JAK1-STAT3-Oct-4 pathway in the conversion of non-stem cancer cells into cancer stem-like cells. Cell Signal. 2013;25:961–9.
Korkaya H, Kim GI, Davis A, Malik F, Henry NL, Ithimakin S, et al. Activation of an IL-6 inflammatory loop mediates trastuzumab resistance in HER2+ breast cancer by expanding the cancer stem cell population. Mol Cell. 2012;47:570–84.
Zhong H, Davis A, Ouzounova M, Carrasco RA, Chen C, Breen S, et al. A novel IL6 antibody sensitizes multiple tumor types to chemotherapy including trastuzumab-resistant tumors. Cancer Res. 2016;76:480–90.
Stravodimou A, Voutsadakis IA. Pre-treatment thrombocytosis as a prognostic marker in metastatic breast cancer. Int J Breast Cancer 2013;2013:Article ID 289563.
Fu Y, Xiong J. MicroRNA-124 enhances response to radiotherapy in human epidermal growth factor receptor 2-positive breast cancer cells by targeting signal transducer and activator of transcription 3. Croat Med J. 2016;57:457–64.
De Cola A, Volpe S, Budani MC, Ferracin M, Lattanzio R, Turdo A, et al. MIR-205-5p-mediated downregulation of ERBB/HER receptors in breast cancer stem cells results in targeted therapy resistance. Cell Death Dis. 2015;6:e1823.
Gupta P, Srivastava SK. HER2 mediated de novo production of TGFβ leads to SNAIL driven epithelial-to-mesenchymal transition and metastasis of breast cancer. Mol Oncol. 2014;8:1532–47.
Tam WL, Lu H, Buikhuisen J, Soh BS, Lim E, Reinhardt F, et al. Protein kinase C α is a central signaling node and therapeutic target for breast cancer stem cells. Cancer Cell. 2013;24:347–64.
Magnifico A, Albano L, Campaner S, Campiglio M, Pilotti S, Ménard S, et al. Protein kinase Cα determines HER2 fate in breast carcinoma cells with HER2 protein overexpression without gene amplification. Cancer Res. 2007;67:5308–17.
Tan M, Li P, Sun M, Yin G, Yu D. Upregulation and activation of PKCα by ErbB2 through Src promotes breast cancer cell invasion that can be blocked by combined treatment with PKCα and Src inhibitors. Oncogene. 2006;25:3286–95.
Oliveira-Ferrer L, Kürschner M, Labitzky V, Wicklein D, Müller V, Lüers G, et al. Prognostic impact of transcription factor Fra-1 in ER-positive breast cancer: contribution to a metastatic phenotype through modulation of tumor cell adhesive properties. J Cancer Res Clin Oncol. 2015;141:1715–26.
Sun L, Burnett J, Gasparyan M, Xu F, Jiang H, Lin CC, et al. Novel cancer stem cell targets during epithelial to mesenchymal transition in PTEN-deficient trastuzumab-resistant breast cancer. Oncotarget. 2016;7:51408–22.
Zhao C, Qiao Y, Jonsson P, Wang J, Xu L, Rouhi P, et al. Genome-wide profiling of AP-1-regulated transcription provides insights into the invasiveness of triple-negative breast cancer. Cancer Res. 2014;74:3983–94.
Kharman-Biz A, Gao H, Ghiasvald R, Zhao C, Zendehdel K, Dahlman-Wright K. Expression of activator protein-1 (AP-1) family members in breast cancer. BMC Cancer. 2013;13:1–10.
Bakiri L, Macho-Maschler S, Custic I, Niemiec J, Guío-Carrión A, Hasenfuss SC, et al. Fra-1/AP-1 induces EMT in mammary epithelial cells by modulating Zeb1/2 and TGFβ expression. Cell Death Differ. 2015;22:336–50.
Lin L, Hutzen B, Lee HF, Peng Z, Wang W, Zhao C, et al. Evaluation of STAT3 signaling in ALDH+ and ALDH+/CD44+/CD24− subpopulations of breast cancer cells. PLoS One. 2013;8:e82821.
Ricardo S, Vieira AF, Gerhard R, Leitão D, Pinto R, Cameselle-Teijeiro JF, et al. Breast cancer stem cell markers CD44, CD24 and ALDH1: expression distribution within intrinsic molecular subtype. J Clin Pathol. 2011;64:937–44.
Da Paula AC, Lopes C. Implications of different cancer stem cell phenotypes in breast cancer. Anticancer Res. 2017;37:2173–83.
Martin-Castillo B, Lopez-Bonet E, Cuyàs E, Viñas G, Pernas S, Dorca J, et al. Cancer stem cell-driven efficacy of trastuzumab (Herceptin): towards a reclassification of clinically HER2-positive breast carcinomas. Oncotarget. 2015;6:32317–38.
Park SY, Lee HE, Li H, Shipitsin M, Gelman R, Polyak K. Heterogeneity for stem cell-related markers according to tumor subtype and histologic stage in breast cancer. Clin Cancer Res. 2010;16:876–87.
Liu S, Cong Y, Wang D, Sun Y, Deng L, Liu Y, et al. Breast cancer stem cells transition between epithelial and mesenchymal states reflective of their normal counterparts. Stem Cell Rep. 2014;2:78–91.
Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell. 2007;1:555–67.
Zhang M, Tsimelzon A, Chang CH, Fan C, Wolff A, Perou CM, et al. Intratumoral heterogeneity in a Trp53-null mouse model of human breast cancer. Cancer Discov. 2015;5:520–33.
Perrone G, Gaeta LM, Zagami M, Nasorri F, Coppola R, Borzomati D, et al. In situ identification of CD44+/CD24− cancer cells in primary human breast carcinomas. PLoS One. 2012;7:e43110.
Seo AN, Lee HJ, Kim EJ, Jang MH, Kim YJ, Kim JH, et al. Expression of breast cancer stem cell markers as predictors of prognosis and response to trastuzumab in HER2-positive breast cancer. Br J Cancer. 2016;114:1109–16.
Boulbes DR, Chauhan GB, Jin Q, Bartholomeusz C, Esteva FJ. CD44 expression contributes to trastuzumab resistance in HER2-positive breast cancer cells. Breast Cancer Res Treat. 2015;151:501–13.
Morath I, Jung C, Lévêque R, Linfeng C, Toillon RA, Warth A, et al. Differential recruitment of CD44 isoforms by ErbB ligands reveals an involvement of CD44 in breast cancer. Oncogene. 2018;37:1472–84.
Chung A, Choi M, Han BC, Bose S, Zhang X, Medina-Kauwe L, et al. Basal protein expression is associated with worse outcome and trastuzumab resistance in HER2+ invasive breast cancer. Clin Breast Cancer. 2015;15:448–57.
Martin-Castillo B, Lopez-Bonet E, Buxó M, Dorca J, Tuca-Rodríguez F, Ruano MA, et al. Cytokeratin 5/6 fingerprinting in HER2-positive tumors identifies a poor prognosis and trastuzumab-resistant basal-HER2 subtype of breast cancer. Oncotarget. 2015;6:7104–22.
Oliveras-Ferraros C, Corominas-Faja B, Cufí S, Vazquez-Martin A, Martin-Castillo B, Iglesias JM, et al. Epithelial-to-mesenchymal transition (EMT) confers primary resistance to trastuzumab (Herceptin). Cell Cycle. 2012;11:4020–32.
Martin-Castillo B, Oliveras-Ferraros C, Vazquez-Martin A, Cufí S, Moreno JM, Corominas-Faja B, et al. Basal/HER2 breast carcinomas. Cell Cycle. 2013;12:225–45.
Arribas J, Baselga J, Pedersen K, Parra-Palau JL. p95HER2 and breast cancer. Cancer Res. 2011;71:1515–9.
Scaltriti M, Rojo F, Ocaña A, Anido J, Guzman M, Cortes J, et al. Expression of p95 HER2, a truncated form of the HER2 receptor, and response to anti-HER2 therapies in breast cancer. J Natl Cancer Inst. 2007;99:628–38.
Sperinde J, Jin X, Banerjee J, Penuel E, Saha A, Diedrich G, et al. Quantitation of p95HER2 in paraffin sections by using a p95-specific antibody and correlation with outcome in a cohort of trastuzumab-treated breast cancer patients. Clin Cancer Res. 2010;16:4226–35.
Zhao M, Ramaswamy B. Mechanisms and therapeutic advances in the management of endocrine-resistant breast cancer. World J Clin Oncol. 2014;5:248–62.
Gilani RA, Kazi AA, Shah P, Schech AJ, Chumsri S, Sabnis G, et al. The importance of HER2 signaling in the tumor-initiating cell population in aromatase inhibitor-resistant breast cancer. Breast Cancer Res Treat. 2012;135:681–92.
Nakanishi T, Chumsri S, Khakpour N, Brodie AH, Leyland-Jones B, Hamburger AW, et al. Side-population cells in luminal-type breast cancer have tumour-initiating cell properties, and are regulated by HER2 expression and signalling. Br J Cancer. 2010;102:815–26.
Rodríguez CE, Berardi DE, Abrigo M, Todaro LB, de Bal KJED, Fiszman GL. Breast cancer stem cells are involved in Trastuzumab resistance through the HER2 modulation in 3D culture. J Cell Biochem. 2018;119:1381–91.
Oak PS, Kopp F, Thakur C, Ellwart JW, Rapp UR, Ullrich A, et al. Combinatorial treatment of mammospheres with trastuzumab and salinomycin efficiently targets HER2-positive cancer cells and cancer stem cells. Int J Cancer. 2012;131:2808–19.
Ithimakin A, Day KC, Malik F, Zen Q, Dawsey SJ, Bersano-Begey TF, et al. HER2 drives luminal breast cancer stem cells in the absence of HER2 amplification: implications for efficacy of trastuzumab. Cancer Res. 2013;73:1635–46.
Wise R, Zolkiewska A. Metalloprotease-dependent activation of EGFR modulates CD44+/CD24− populations in triple negative breast cancer cells through the MEK/ERK pathway. Breast Cancer Res Treat. 2017;166:421–33.
Hosonaga M, Arima Y, Sugihara E, Kohno N, Saya H. Expression of CD24 is associated with HER2 expression and supports HER2-Akt signaling in HER2-positive breast cancer cells. Cancer Sci. 2014;105:779–87.
Kwon MJ, Han J, Seo JH, Song K, Jeong HM, Choi JS, et al. CD24 overexpression is associated with poor prognosis in luminal A and triple-negative breast cancer. PLoS One. 2015;10:e0139112.
Savage P, Blanchet-Cohen A, Revil T, Badescu D, Saleh SMI, Wang YC, et al. A targetable EGFR-dependent tumor-initiating program in breast cancer. Cell Rep. 2017;21:1140–9.
Xia W, Petricoin EF 3rd, Zhao S, Liu L, Osada T, Chen Q, et al. An heregulin-EGFR-HER3 autocrine signaling axis can mediate acquired lapatinib resistance in HER2+ breast cancer models. Breast Cancer Res. 2013;15:R85.
Nieto MA, Huang RY, Jackson RA, Thiery JP. EMT: 2016. Cell. 2016;2016(166):21–45.
Lambert AW, Pattabiraman DR, Weinberg RA. Emerging biological principles of metastasis. Cell. 2017;168:670–91.
Lawson DA, Bhakta NR, Kessenbrock K, Prummel KD, Yu Y, Takai K, et al. Single-cell analysis reveals a stem-cell program in human metastatic breast cancer cells. Nature. 2015;526:131–5.
Grigore A, Jolly M, Jia D, Farach-Carson M, Levine H. Tumor budding: the name is EMT. Partial EMT. J Clin Med. 2016;5:51.
Liang F, Cao W, Wang Y, Li L, Zhang G, Wang Z. The prognostic value of tumor budding in invasive breast cancer. Pathol Res Pract. 2013;209:269–75.
Laedrach C, Salhia B, Cihoric N, Zlobec I, Tapia C. Immunophenotypic profile of tumor buds in breast cancer. Pathol Res Pract. 2018;214:25–9.
Krawczyk N, Meier-Stiegen F, Banys M, Neubauer H, Ruckhaeberle E, Fehm T. Expression of stem cell and epithelial–mesenchymal transition markers in circulating tumor cells of breast cancer patients. Biomed Res Int. 2014;2014:415721.
Zhang S, Wu T, Peng X, Liu J, Liu F, Wu S, et al. Mesenchymal phenotype of circulating tumor cells is associated with distant metastasis in breast cancer patients. Cancer Manag Res. 2017;9:691–700.
Yu M, Bardia A, Wittner BS, Stott SL, Smas ME, Ting DT, et al. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science. 2013;339:580–4.
Wallwiener M, Hartkopf AD, Riethdorf S, Nees J, Sprick MR, Schönfisch B, et al. The impact of HER2 phenotype of circulating tumor cells in metastatic breast cancer: a retrospective study in 107 patients. BMC Cancer. 2015;15:1–7.
Pestrin M, Bessi S, Galardi F, Truglia M, Biggeri A, Biagioni C, et al. Correlation of HER2 status between primary tumors and corresponding circulating tumor cells in advanced breast cancer patients. Breast Cancer Res Treat. 2009;118:523–30.
Aktas B, Kasimir-Bauer S, Müller V, Janni W, Fehm T, Wallwiener D, et al. Comparison of the HER2, estrogen and progesterone receptor expression profile of primary tumor, metastases and circulating tumor cells in metastatic breast cancer patients. BMC Cancer. 2016;16:1–8.
Fehm T, Müller V, Aktas B, Janni W, Schneeweiss A, Stickeler E, et al. HER2 status of circulating tumor cells in patients with metastatic breast cancer: a prospective, multicenter trial. Breast Cancer Res Treat. 2010;124:403–12.
Jaeger BAS, Neugebauer J, Andergassen U, Melcher C, Schochter F, Mouarrawy D, et al. The HER2 phenotype of circulating tumor cells in HER2-positive early breast cancer: a translational research project of a prospective randomized phase III trial. PLoS One. 2017;12:e0173593.
Krishnamurthy S, Bischoff F, Ann Mayer J, Wong K, Pham T, Kuerer H, et al. Discordance in HER2 gene amplification in circulating and disseminated tumor cells in patients with operable breast cancer. Cancer Med. 2013;2:226–33.
Agelaki S, Dragolia M, Markomanolaki H, Alkahtani S, Stournaras C, Georgoulias V, et al. Phenotypic characterization of circulating tumor cells in triple negative breast cancer patients. Oncotarget. 2017;8:5309–22.
Jordan NV, Bardia A, Wittner BS, Benes C, Ligorio M, Zheng Y, et al. HER2 expression identifies dynamic functional states within circulating breast cancer cells. Nature. 2016;537:102–6.
Nishimura R, Osako T, Okumura Y, Tashima R, Toyozumi Y, Arima N. Changes in the ER, PgR, HER2, p53 and Ki-67 biological markers between primary and recurrent breast cancer: discordance rates and prognosis. World J Surg Oncol. 2011;9:1–7.
Rossi S, Basso M, Strippoli A, Dadduzio V, Cerchiaro E, Barile R, et al. Hormone receptor status and HER2 expression in primary breast cancer compared with synchronous axillary metastases or recurrent metastatic disease. Clin Breast Cancer. 2015;15:307–12.
Braun S, Vogl FD, Naume B, Janni W, Osborne MP, Coombes RC, et al. A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med. 2005;353:793–802.
Balic M, Lin H, Young L, Hawes D, Giuliano A, McNamara G, et al. Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype. Clin Cancer Res. 2006;12:5615–21.
Jäger BAS, Finkenzeller C, Bock C, Majunke L, Jueckstock JK, Andergassen U, et al. Estrogen receptor and HER2 status on disseminated tumor cells and primary tumor in patients with early breast cancer. Transl Oncol. 2015;8:509–16.
Hartkopf AD, Banys M, Meier-Stiegen F, Hahn M, Röhm C, Hoffmann J, et al. The HER2 status of disseminated tumor cells in the bone marrow of early breast cancer patients is independent from primary tumor and predicts higher risk of relapse. Breast Cancer Res Treat. 2013;138:509–17.
Becker S, Becker-Pergola G, Fehm T, Wallwiener D, Solomayer EF. Her2 expression on disseminated tumor cells from bone marrow of breast cancer patients. Anticancer Res. 2005;25:2171–5.
Korkaya H, Paulson A, Charafe-Jauffret E, Ginestier C, Brown M, Dutcher J, et al. Regulation of mammary stem/progenitor cells by PTEN/Akt/β-catenin signaling. PLoS Biol. 2009;7:e1000121.
André F, O’Regan R, Ozguroglu M, Toi M, Xu B, Jerusalem G, et al. Everolimus for women with trastuzumab-resistant, HER-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 2014;15:580–91.
Davies BR, Greenwood H, Dudley P, Crafter C, Yu DH, Zhang J, et al. Preclinical pharmacology of AZD5363, an Inhibitor of AKT: pharmacodynamics, antitumor activity, and correlation of monotherapy activity with genetic background. Mol Cancer Ther. 2012;11:873–87.
Will M, Qin AC, Toy W, Yao Z, Rodrik-Outmezguine V, Schneider C, et al. Rapid induction of apoptosis by PI3K inhibitors is dependent upon their transient inhibition of RAS-ERK signaling. Cancer Discov. 2014;4:334–48.
Saura C, Bendell J, Jerusalem G, Su S, Ru Q, De Buck S, et al. Phase lb study of buparlisib plus trastuzumab in patients with HER2-positive advanced or metastatic breast cancer that has progressed on trastuzumab-based therapy. Clin Cancer Res. 2014;20:1935–45.
Loibl S, de la Pena L, Nekljudova V, Zardavas D, Michiels S, Denkert C, et al. Neoadjuvant buparlisib plus trastuzumab and paclitaxel for women with HER2+ primary breast cancer: a randomised, double-blind, placebo-controlled phase II trial (NeoPHOEBE). Eur J Cancer. 2017;85:133–45.
Wang WCH, Juan AH, Panebra A, Liggett SB. MicroRNA let-7 establishes expression of beta2-adrenergic receptors and dynamically down-regulates agonist-promoted down-regulation. Proc Natl Acad Sci USA. 2011;108:6246–51.
Shi M, Liu D, Duan H, Qian L, Wang L, Niu L, et al. The β2-adrenergic receptor and Her2 comprise a positive feedback loop in human breast cancer cells. Breast Cancer Res Treat. 2011;125:351–62.
Cufí S, Corominas-Faja B, Vazquez-Martin A, Oliveras-Ferraros C, Dorca J, Bosch-Barrera J, et al. Metformin-induced preferential killing of breast cancer initiating CD44+ CD24−/low cells is sufficient to overcome primary resistance to trastuzumab in HER2+ human breast cancer xenografts. Oncotarget. 2012;3:395–8.
Yamauchi T, Espinosa Fernandez JR, Imamura CK, Yamauchi H, Jinno H, Takahashi M, et al. Dynamic changes in CD44v-positive cells after preoperative anti-HER2 therapy and its correlation with pathologic complete response in HER2-positive breast cancer. Oncotarget. 2018;9:6872–82.
Conflict of interest
The author declares no conflicts of interest regarding this paper.
This paper involves no human participants or animals.
No informed consent was necessary.
About this article
Cite this article
Voutsadakis, I.A. HER2 in stemness and epithelial–mesenchymal plasticity of breast cancer. Clin Transl Oncol 21, 539–555 (2019). https://doi.org/10.1007/s12094-018-1961-x
- Breast cancer
- Cancer stem cells
- Epithelial to mesenchymal transition