Top

Journal of Mammary Gland Biology and Neoplasia

Published in:

01-06-2008

ERBB3/HER3 and ERBB2/HER2 Duet in Mammary Development and Breast Cancer

Author: David F. Stern

Published in: Journal of Mammary Gland Biology and Neoplasia | Issue 2/2008

Abstract

ERBB3/HER3 is one of the four members of the epidermal growth factor receptor (ERBB) family. It is activated by binding to ligands Neuregulin-1 and Neuregulin-2. Since ERBB3 lacks intrinsic kinase activity, signal transduction occurs through formation of heterodimers with EGFR, ERBB2, and ERBB4. ERBB3 is a signaling specialist since it has six binding sites for the p85 SH2 adapter subunit of phosphoinositide 3’ kinases. These lipid kinases coordinate regulation of metabolism, cell size, proliferation, survival, and angiogenesis. Not surprisingly, ERBB3 signaling has been linked to cancer etiology and progression. In breast cancer, the partnership of ERBB2 and ERBB3 may be crucial for the aggressive properties of cancers with ERBB2 amplification, and may contribute to pre-existing and acquired resistance to therapy. This partnership creates opportunities for improving efficacy of ERBB-targeted pharmaceuticals, by interfering with coupling of ERBB2 to ERBB3 through dimerization inhibitors, and by use of therapeutic compounds that target AKT-dependent pathways activated through ERBB3. Additional therapeutic opportunities may be identified through better understanding of how ERBBs are regulated and deployed in normal mammary gland processes. Work using mouse models has identified the main processes regulated by each of the four ERBBs, which has practical implications in understanding breast cancer etiology, and eventual development of better prognostic, predictive, and therapeutic tools.

Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 2005;5(5):341–54.PubMedCrossRef

Stern DF. ErbBs in mammary development. Exp Cell Res 2003;284(1):89–98.PubMedCrossRef

Sternlicht MD. Key stages in mammary gland development: the cues that regulate ductal branching morphogenesis. Breast Cancer Res 2006;8(1):201.PubMedCrossRef

Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr., Davidson NE, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353(16):1673–84.PubMedCrossRef

Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353(16):1659–72.PubMedCrossRef

Siziopikou KP, Cobleigh M. The basal subtype of breast carcinomas may represent the group of breast tumors that could benefit from EGFR-targeted therapies. Breast 2007;16(1):104–7.PubMedCrossRef

Gullick WJ. c-erbB-4/HER4: friend or foe. J Pathol 2003;200(3):279–81.PubMedCrossRef

Muraoka-Cook RS, Sandahl M, Husted C, Hunter D, Miraglia L, Feng SM, et al. The intracellular domain of ErbB4 induces differentiation of mammary epithelial cells. Mol Biol Cell 2006;17(9):4118–29.PubMedCrossRef

Junttila TT, Sundvall M, Lundin M, Lundin J, Tanner M, Harkonen P, et al. Cleavable ErbB4 isoform in estrogen receptor-regulated growth of breast cancer cells. Cancer Res 2005;65(4):1384–93.PubMedCrossRef

10.

Riese DJ II, Stern DF. Specificity within the EGF/ErbB receptor family signaling network. BioEssays 1998;20:41–8.PubMedCrossRef

11.

Stern DF, Heffernan PA, Weinberg RA. p185, a product of the neu proto-oncogene, is a receptorlike protein associated with tyrosine kinase activity. Mol Cell Biol 1986;6(5):1729–40.PubMed

12.

Karunagaran D, Tzahar E, Beerli R, Chen X, Graus-Porta D, Ratzkin B, et al. ErbB2 is a common auxiliary subunit of NDF and EGF receptors: implications for breast cancer. EMBO J 1996;15:254–64.PubMed

13.

Riese D II, Komurasaki T, Plowman GD, Stern DF. Activation of ErbB4 by the bifunctional EGF family hormone epiregulin is regulated by ErbB2. J Biol Chem 1998;273:11288–94.PubMedCrossRef

14.

Burgess AW, Cho HS, Eigenbrot C, Ferguson KM, Garrett TP, Leahy DJ, et al. An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors. Mol Cell 2003;12(3):541–52.PubMedCrossRef

15.

Qiu C, Tarrant MK, Choi SH, Sathyamurthy A, Bose R, Banjade S, et al. Mechanism of Activation and inhibition of the HER4/ErbB4 Kinase. Structure 2008;16(3):460–7.PubMedCrossRef

16.

Zhang X, Gureasko J, Shen K, Cole PA, Kuriyan J. An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor. Cell 2006;125(6):1137–49.PubMedCrossRef

17.

Fischer OM, Hart S, Gschwind A, Ullrich A. EGFR signal transactivation in cancer cells. Biochem Soc Trans 2003;31(Pt 6):1203–8.PubMed

18.

Carraway KL, Perez A, Idris N, Jepson S, Arango M, Komatsu M, et al. Muc4/sialomucin complex, the intramembrane ErbB2 ligand, in cancer and epithelia: to protect and to survive. Prog Nucleic Acid Res Mol Biol 2002;71:149–85.PubMedCrossRef

19.

Pochampalli MR, el Bejjani RM, Schroeder JA. MUC1 is a novel regulator of ErbB1 receptor trafficking. Oncogene 2007;26(12):1693–701.PubMedCrossRef

20.

Hamburger AW. The Role of ErbB3 and its binding partners in breast cancer progression and resistance to hormone and tyrosine kinase directed therapies. J Mammary Gland Biol Neoplasia. 2008 (this issue) DOI 10.007/s10911-008-9077-5.

21.

Hendriks BS, Opresko LK, Wiley HS, Lauffenburger D. Quantitative analysis of HER2-mediated effects on HER2 and epidermal growth factor receptor endocytosis: distribution of homo- and heterodimers depends on relative HER2 levels. J Biol Chem 2003;278(26):23343–51.PubMedCrossRef

22.

Holbro T, Beerli RR, Maurer F, Koziczak M, Barbas CF 3rd, Hynes NE. The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation. Proc Natl Acad Sci U S A 2003;100(15):8933–8.PubMedCrossRef

23.

Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001;2(2):127–37.PubMedCrossRef

24.

Zhou W, Carpenter G. Heregulin-dependent translocation and hyperphosphorylation of ErbB-2. Oncogene 2001;20(29):3918–20.PubMedCrossRef

25.

Ni C, Murphy M, Golde T, Carpenter G. g-Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase. Science 2001;294:2179–81.PubMedCrossRef

26.

Arasada RR, Carpenter G. Secretase-dependent tyrosine phosphorylation of Mdm2 by the ErbB-4 intracellular domain fragment. J Biol Chem 2005;280(35):30783–7.PubMedCrossRef

27.

Linggi B, Carpenter G. ErbB-4 s80 intracellular domain abrogates ETO2-dependent transcriptional repression. J Biol Chem 2006;281(35):25373–80.PubMedCrossRef

28.

Sardi SP, Murtie J, Koirala S, Patten BA, Corfas G. Presenilin-dependent ErbB4 nuclear signaling regulates the timing of astrogenesis in the developing brain. Cell 2006;127(1):185–97.PubMedCrossRef

29.

Naresh A, Long W, Vidal GA, Wimley WC, Marrero L, Sartor CI, et al. The ERBB4/HER4 intracellular domain 4ICD is a BH3-only protein promoting apoptosis of breast cancer cells. Cancer Res 2006;66(12):6412–20.PubMedCrossRef

30.

Vidal GA, Naresh A, Marrero L, Jones FE. Presenilin-dependent gamma-secretase processing regulates multiple ERBB4/HER4 activities. J Biol Chem 2005;280(20):19777–83.PubMedCrossRef

31.

Aqeilan RI, Donati V, Palamarchuk A, Trapasso F, Kaou M, Pekarsky Y, et al. WW domain-containing proteins, WWOX and YAP, compete for interaction with ErbB-4 and modulate its transcriptional function. Cancer Res 2005;65(15):6764–72.PubMedCrossRef

32.

Omerovic J, Santangelo L, Puggioni EM, Marrocco J, Dall'Armi C, Palumbo C, et al. The E3 ligase Aip4/Itch ubiquitinates and targets ErbB-4 for degradation. FASEB J 2007;21(11):2849–62.PubMedCrossRef

33.

Sundvall M, Veikkolainen V, Tvorogov D, ELenius K. Cell death or survival promoted by alternative isoforms of ErbB4. In: American Association for Cancer Research, annual meeting; 2007; 2007. p. 1239.

34.

Carraway KI, Soltoff S, Diamonti A, Cantley L. Heregulin stimulates mitogenesis and phosphatidylinositol 3-kinase in mouse fibroblasts transfected with erbB2/neu and erbB3. J Biol Chem 1995;270:7111–8.PubMedCrossRef

35.

Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell 2007;129(7):1261–74.PubMedCrossRef

36.

Brugge J, Hung MC, Mills GB. A new mutational AKTivation in the PI3K pathway. Cancer Cell 2007;12(2):104–7.PubMedCrossRef

37.

Sordella R, Bell DW, Haber DA, Settleman J. Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 2004;305(5687):1163–7.PubMedCrossRef

38.

Sternlicht MD, Sunnarborg SW, Kouros-Mehr H, Yu Y, Lee DC, Werb Z. Mammary ductal morphogenesis requires paracrine activation of stromal EGFR via ADAM17-dependent shedding of epithelial amphiregulin. Development 2005;132(17):3923–33.PubMedCrossRef

39.

Howard B, Panchal H, McCarthy A, Ashworth A. Identification of the scaramanga gene implicates Neuregulin3 in mammary gland specification. Genes Dev 2005;19(17):2078–90.PubMedCrossRef

40.

Tidcombe H, Jackson-Fisher A, Mathers K, Stern DF, Gassmann M, Golding JP. Neural and mammary gland defects in ErbB4 knockout mice genetically rescued from embryonic lethality. Proc Natl Acad Sci U S A 2003;100(14):8281–6.PubMedCrossRef

41.

Schroeder JA, Lee DC. Dynamic expression and activation of ERBB receptors in the developing mouse mammary gland. Cell Growth Differ 1998;9:451–64.PubMed

42.

Luetteke N, Qiu T, Fenton S, Troyer K, Riedel R, Chang A, et al. Targeted inactivation of the EGF and amphiregulin genes reveals distinct roles for EGF receptor ligands in mouse mammary gland development. Development 1999;126:2739–50.PubMed

43.

Wiesen J, Young P, Werb Z, Cunha G. Signaling through the stromal epidermal growth factor receptor is necessary for mammary ductal development. Development 1999;126:335–44.PubMed

44.

Sebastian J, Richards RG, Walker MP, Wiesen JF, Werb Z, Derynck R, et al. Activation and function of the epidermal growth factor receptor and erbB-2 during mammary gland morphogenesis. Cell Growth Differ 1998;9:777–85.PubMed

45.

Jackson-Fisher AJ, Bellinger G, Ramabhadran R, Morris JK, Lee KF, Stern DF. ErbB2 is required for ductal morphogenesis of the mammary gland. Proc Natl Acad Sci U S A 2004;101(49):17138–43.PubMedCrossRef

46.

Andrechek ER, White D, Muller WJ. Targeted disruption of ErbB2/Neu in the mammary epithelium results in impaired ductal outgrowth. Oncogene 2005;24(5):932–7.PubMedCrossRef

47.

Jones FE, Jerry DJ, Guarino BC, Andrews GC, Stern DF. Heregulin induces in vivo proliferation and differentiation of mammary epithelium into secretory lobuloalveoli. Cell Growth Differ 1996;7:1031–8.PubMed

48.

Qu S, Rinehart C, Wu HH, Wang SE, Carter B, Xin H, et al. Gene targeting of ErbB3 using a Cre-mediated unidirectional DNA inversion strategy. Genesis 2006;44(10):477–86.PubMedCrossRef

49.

Jones F, Stern D. Expression of dominant-negative ErbB2 in the mammary gland of transgenic mice reveals a role in lobuloalveolar development and lactation. Oncogene 1999;18:3481–90.PubMedCrossRef

50.

Jones FE, Welte T, Fu X-Y, Stern DF. ErbB4 signaling in the mammary gland is required for lobuloalveolar development and Stat5 activation during lactation. J Cell Biol 1999;147:77–88.PubMedCrossRef

51.

Long W, Wagner KU, Lloyd KC, Binart N, Shillingford JM, Hennighausen L, et al. Impaired differentiation and lactational failure of Erbb4-deficient mammary glands identify ERBB4 as an obligate mediator of STAT5. Development 2003;130(21):5257–68.PubMedCrossRef

52.

Suo Z, Risberg B, Kalsson M, Willman K, Tierens A, Skovlund E, et al. EGFR family expression in breast carcinomas. c-erbB-2 and c-erbB-4 receptors have different effects on survival. J Pathol 2002;196:17–25.PubMedCrossRef

53.

Barnes NL, Khavari S, Boland GP, Cramer A, Knox WF, Bundred NJ. Absence of HER4 expression predicts recurrence of ductal carcinoma in situ of the breast. Clin Cancer Res 2005;11(6):2163–8.PubMedCrossRef

54.

Lodge AJ, Anderson JJ, Gullick WJ, Haugk B, Leonard RC, Angus B. Type 1 growth factor receptor expression in node positive breast cancer: adverse prognostic significance of c-erbB-4. J Clin Pathol 2003;56(4):300–4.PubMedCrossRef

55.

Hoadley KA, Weigman VJ, Fan C, Sawyer LR, He X, Troester MA, et al. EGFR associated expression profiles vary with breast tumor subtype. BMC Genomics 2007;8:258.PubMedCrossRef

56.

Gordon MS, Matei D, Aghajanian C, Matulonis UA, Brewer M, Fleming GF, et al. Clinical activity of pertuzumab (rhuMAb 2C4), a HER dimerization inhibitor, in advanced ovarian cancer: potential predictive relationship with tumor HER2 activation status. J Clin Oncol 2006;24(26):4324–32.PubMedCrossRef

57.

Riese DJ II, van Raaij TM, Plowman GD, Andrews GC, Stern DF. Cellular response to neuregulins is governed by complex interactions of the erbB receptor family. Mol Cell Biol 1995;15:5770–6.PubMed

58.

Pinkas-Kramarski R, Soussan L, Waterman H, Levkowitz G, Alroy I, Klapper L, et al. Diversification of Neu differentiation factor and epidermal growth factor signaling by combinatorial receptor interactions. EMBO J 1996;15:2452–67.PubMed

59.

Siegel P, Ryan E, Cardiff R, Muller W. Elevated expression of activated forms of Neu/ErbB-2 and ErbB-3 are involved in the induction of mammary tumors in transgenic mice: implications for human breast cancer. EMBO J 1999;18:2149–64.PubMedCrossRef

60.

Piechocki MP, Yoo GH, Dibbley SK, Lonardo F. Breast cancer expressing the activated HER2/neu is sensitive to gefitinib in vitro and in vivo and acquires resistance through a novel point mutation in the HER2/neu. Cancer Res 2007;67(14):6825–43.PubMedCrossRef

61.

Tovey SM, Witton CJ, Bartlett JM, Stanton PD, Reeves JR, Cooke TG. Outcome and human epidermal growth factor receptor (HER) 1–4 status in invasive breast carcinomas with proliferation indices evaluated by bromodeoxyuridine labelling. Breast Cancer Res 2004;6(3):R246–51.PubMedCrossRef

62.

Witton CJ, Reeves JR, Going JJ, Cooke TG, Bartlett JM. Expression of the HER1–4 family of receptor tyrosine kinases in breast cancer. J Pathol 2003;200(3):290–7.PubMedCrossRef

63.

Liu B, Ordonez-Ercan D, Fan Z, Edgerton SM, Yang X, Thor AD. Downregulation of erbB3 abrogates erbB2-mediated tamoxifen resistance in breast cancer cells. Int J Cancer 2007;120(9):1874–82.PubMedCrossRef

64.

Zaczek A, Welnicka-Jaskiewicz M, Bielawski KP, Jaskiewicz J, Badzio A, Olszewski W, et al. Gene copy numbers of HER family in breast cancer. J Cancer Res Clin Oncol 2008;134(2):271–9.PubMedCrossRef

65.

Bieche I, Onody P, Tozlu S, Driouch K, Vidaud M, Lidereau R. Prognostic value of ERBB family mRNA expression in breast carcinomas. Int J Cancer 2003;106(5):758–65.PubMedCrossRef

66.

Sassen A, Rochon J, Wild P, Hartmann A, Hofstaedter F, Schwarz S, et al. Cytogenetic analysis of HER1/EGFR, HER2, HER3 and HER4 in 278 breast cancer patients. Breast Cancer Res 2008;10(1):R2.PubMedCrossRef

67.

Revillion F, Lhotellier V, Hornez L, Bonneterre J, Peyrat JP. ErbB/HER ligands in human breast cancer, and relationships with their receptors, the bio-pathological features and prognosis. Ann Oncol 2008;19(1):73–80.PubMedCrossRef

68.

Menendez JA, Lupu R. Transphosphorylation of kinase-dead HER3 and breast cancer progression: a new standpoint or an old concept revisited. Breast Cancer Res 2007;9(5):111.PubMedCrossRef

69.

Hutcheson IR, Knowlden JM, Hiscox SE, Barrow D, Gee JM, Robertson JF, et al. Heregulin beta1 drives gefitinib-resistant growth and invasion in tamoxifen-resistant MCF-7 breast cancer cells. Breast Cancer Res 2007;9(4):R50.PubMedCrossRef

70.

Osipo C, Meeke K, Cheng D, Weichel A, Bertucci A, Liu H, et al. Role for HER2/neu and HER3 in fulvestrant-resistant breast cancer. Int J Oncol 2007;30(2):509–20.PubMed

71.

Ritter CA, Perez-Torres M, Rinehart C, Guix M, Dugger T, Engelman JA, et al. Human breast cancer cells selected for resistance to trastuzumab in vivo overexpress epidermal growth factor receptor and ErbB ligands and remain dependent on the ErbB receptor network. Clin Cancer Res 2007;13(16):4909–19.PubMedCrossRef

72.

Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 2004;6(2):117–27.PubMedCrossRef

73.

Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, Beelen K, et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 2007;12(4):395–402.PubMedCrossRef

74.

Lu Y, Zi X, Pollak M. Molecular mechanisms underlying IGF-I-induced attenuation of the growth-inhibitory activity of trastuzumab (Herceptin) on SKBR3 breast cancer cells. Int J Cancer 2004;108(3):334–41.PubMedCrossRef

75.

Smith BL, Chin D, Maltzman W, Crosby K, Hortobagyi GN, Bacus SS. The efficacy of Herceptin therapies is influenced by the expression of other erbB receptors, their ligands and the activation of downstream signalling proteins. Br J Cancer 2004;91(6):1190–4.PubMed

76.

Nahta R, Yuan LX, Zhang B, Kobayashi R, Esteva FJ. Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells. Cancer Res 2005;65(23):11118–28.PubMedCrossRef

77.

Chakraborty AK, Liang K, DiGiovanna MP. Co-targeting insulin-like growth factor I receptor and HER2: dramatic effects of HER2 inhibitors on nonoverexpressing breast cancer. Cancer Res 2008;68(5):1538–45.PubMedCrossRef

78.

Sergina NV, Rausch M, Wang D, Blair J, Hann B, Shokat KM, et al. Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature 2007;445(7126):437–41.PubMedCrossRef

79.

Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 2007;316(5827):1039–43.PubMedCrossRef

80.

Huang PH, Mukasa A, Bonavia R, Flynn RA, Brewer ZE, Cavenee WK, et al. Quantitative analysis of EGFRvIII cellular signaling networks reveals a combinatorial therapeutic strategy for glioblastoma. Proc Natl Acad Sci U S A 2007;104(31):12867–72.PubMedCrossRef

Title: ERBB3/HER3 and ERBB2/HER2 Duet in Mammary Development and Breast Cancer
Author: David F. Stern
Publication date: 01-06-2008
Publisher: Springer US
Published in: Journal of Mammary Gland Biology and Neoplasia / Issue 2/2008
Print ISSN: 1083-3021
Electronic ISSN: 1573-7039
DOI: https://doi.org/10.1007/s10911-008-9083-7

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2008

The Role of NRG3 in Mammary Development

Role of ErbB4 in Breast Cancer

Amphiregulin as a Novel Target for Breast Cancer Therapy

ErbB4/HER4: Role in Mammary Gland Development, Differentiation and Growth Inhibition

The Role of ErbB3 and its Binding Partners in Breast Cancer Progression and Resistance to Hormone and Tyrosine Kinase Directed Therapies

The Epidermal Growth Factor Family of Ligands and Receptors Grows and Grows

Keynote webinar | Spotlight on antibody–drug conjugates in cancer