Uncoupling of PI3K from ErbB3 impairs mammary gland development but does not impact on ErbB2-induced mammary tumorigenesis.

The formation of ErbB2/ErbB3 heterodimers plays a critical role in ErbB2-mediated signaling in both normal mammary development and mammary tumor progression. Through 7 phosphoinositide 3-kinase (PI3K) phosphotyrosine-binding sites, ErbB3 is able to recruit PI3K and initiate the PI3K/AKT signaling pathway. To directly explore the importance of the ErbB3/PI3K pathway in mammary development and tumorigenesis, we generated a mouse model that carries a mutant ErbB3 allele lacking the seven known PI3K-binding sites (ErbB3(Δ85)). Mice homozygous for the ErbB3(Δ85) allele exhibited an initial early growth defect and a dramatic impairment of mammary epithelial outgrowth. Although homozygous adult mice eventually recovered from the growth defect, their mammary glands continued to manifest the mammary outgrowth and lactation defects throughout their adult life. Interestingly, despite the presence of a profound mammary gland defect, all of the female ErbB3Δ85 mice developed metastatic ErbB2-induced mammary tumors secondary to mammary epithelial expression of an activated ErbB2 oncogene capable of compensatory PI3K signaling from both EGF receptor and ErbB2. Our findings therefore indicate that, although ErbB3-associated PI3K activity is critical for mammary development, it is dispensable for ErbB2-induced mammary tumor progression.

[1]  T. Pawson,et al.  The ShcA SH2 domain engages a 14-3-3/PI3′K signaling complex and promotes breast cancer cell survival , 2012, Oncogene.

[2]  C. Arteaga,et al.  ErbB3 ablation impairs PI3K/Akt-dependent mammary tumorigenesis. , 2011, Cancer research.

[3]  Carlos L. Arteaga,et al.  Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors , 2011, Proceedings of the National Academy of Sciences.

[4]  J. McManaman,et al.  Heterotrimerization of the growth factor receptors erbB2, erbB3, and insulin-like growth factor-i receptor in breast cancer cells resistant to herceptin. , 2010, Cancer research.

[5]  J. Baselga,et al.  Novel anticancer targets: revisiting ERBB2 and discovering ERBB3 , 2009, Nature Reviews Cancer.

[6]  D. Stern,et al.  ErbB3 is required for ductal morphogenesis in the mouse mammary gland , 2008, Breast Cancer Research.

[7]  D. Stern.  ERBB3/HER3 and ERBB2/HER2 Duet in Mammary Development and Breast Cancer , 2008, Journal of Mammary Gland Biology and Neoplasia.

[8]  R. Cardiff,et al.  Mammary epithelial-specific disruption of the focal adhesion kinase blocks mammary tumor progression , 2007, Proceedings of the National Academy of Sciences.

[9]  M. Moasser.  The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis , 2007, Oncogene.

[10]  M. Moasser,et al.  Targeting HER proteins in cancer therapy and the role of the non-target HER3 , 2007, British Journal of Cancer.

[11]  Robert D. Cardiff,et al.  Insights from transgenic mouse models of ERBB2-induced breast cancer , 2007, Nature Reviews Cancer.

[12]  W. Muller,et al.  The phosphatidyl inositol 3-kinase signaling network: implications for human breast cancer , 2007, Oncogene.

[13]  K. Shokat,et al.  Escape from HER family tyrosine kinase inhibitor therapy by the kinase inactive HER3 , 2007, Nature.

[14]  Ji Luo,et al.  The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism , 2006, Nature Reviews Genetics.

[15]  L. Anderson,et al.  Alternate paths from epidermal growth factor receptor to Akt in malignant versus nontransformed lung epithelial cells: ErbB3 versus Gab1. , 2005, American journal of respiratory cell and molecular biology.

[16]  H. Lane,et al.  ERBB Receptors and Cancer: The Complexity of Targeted Inhibitors , 2005, Nature Reviews Cancer.

[17]  M. Mann,et al.  Phosphotyrosine interactome of the ErbB-receptor kinase family , 2005, Molecular systems biology.

[18]  E. Andrechek,et al.  Targeted disruption of ErbB2/Neu in the mammary epithelium results in impaired ductal outgrowth , 2005, Oncogene.

[19]  D. Stern,et al.  ErbB2 is required for ductal morphogenesis of the mammary gland. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[20]  R. Cardiff,et al.  Epidermal growth factor receptor-dependent activation of Gab1 is involved in ErbB-2-mediated mammary tumor progression , 2003, Oncogene.

[21]  F. Maurer,et al.  The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[22]  A. Citri,et al.  The deaf and the dumb: the biology of ErbB-2 and ErbB-3. , 2003, Experimental cell research.

[23]  D. Stern,et al.  ErbBs in mammary development. , 2003, Experimental cell research.

[24]  C. Mounier,et al.  Epidermal Growth Factor-induced DNA Synthesis , 2003, The Journal of Biological Chemistry.

[25]  Brian Higgins,et al.  Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. , 2002, Cancer cell.

[26]  S. Eccles.  The Role of c-erbB-2/HER2/neu in Breast Cancer Progression and Metastasis , 2001, Journal of Mammary Gland Biology and Neoplasia.

[27]  Y. Yarden,et al.  Untangling the ErbB signalling network , 2001, Nature Reviews Molecular Cell Biology.

[28]  M. Holzenberger,et al.  A targeted partial invalidation of the insulin-like growth factor I receptor gene in mice causes a postnatal growth deficit. , 2000, Endocrinology.

[29]  R. Neve,et al.  Effects of oncogenic ErbB2 on G1 cell cycle regulators in breast tumour cells , 2000, Oncogene.

[30]  K. Darcy,et al.  Changes in ErbB2 (her-2/neu), ErbB3, and ErbB4 during Growth, Differentiation, and Apoptosis of Normal Rat Mammary Epithelial Cells , 2000, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[31]  D. Stern,et al.  Expression of dominant-negative ErbB2 in the mammary gland of transgenic mice reveals a role in lobuloalveolar development and lactation , 1999, Oncogene.

[32]  R. Cardiff,et al.  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 , 1999, The EMBO journal.

[33]  Kuala Lumpur Malaysia,et al.  Expression of c-erbB3 protein in primary breast carcinomas. , 1998, British Journal of Cancer.

[34]  D. Riethmacher,et al.  Severe neuropathies in mice with targeted mutations in the ErbB3 receptor , 1997, Nature.

[35]  M. Moran,et al.  Distinct tyrosine autophosphorylation sites negatively and positively modulate neu-mediated transformation , 1997, Molecular and cellular biology.

[36]  J. Luck,et al.  Clinical and prognostic significance of the expression of the c-erbB-2 and c-erbB-3 oncoproteins in primary and metastatic malignant melanomas and breast carcinomas. , 1997, Anticancer research.

[37]  Kuo-Fen Lee,et al.  Requirement for neuregulin receptor erbB2 in neural and cardiac development , 1995, Nature.

[38]  K. Herrup,et al.  Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype. , 1995, Science.

[39]  N. Hynes,et al.  The biology of erbB-2/neu/HER-2 and its role in cancer. , 1994, Biochimica et biophysica acta.

[40]  C. Quinn,et al.  c‐erbB‐3 protein expression in human breast cancer: comparison with other tumour variables and survival , 1994, Histopathology.

[41]  L. Cantley,et al.  ErbB3 is involved in activation of phosphatidylinositol 3-kinase by epidermal growth factor , 1994, Molecular and cellular biology.

[42]  W. Gullick,et al.  Identification of c‐erbB‐3 binding sites for phosphatidylinositol 3′‐kinase and SHC using an EGF receptor/c‐erbB‐3 chimera. , 1994, The EMBO journal.

[43]  Andrea Richardson,et al.  A role for the scaffolding adapter GAB2 in breast cancer , 2006, Nature Medicine.

[44]  David C. Lee,et al.  Regulation of Mouse Mammary Gland Development and Tumorigenesis by the ERBB Signaling Network , 2004, Journal of Mammary Gland Biology and Neoplasia.

[45]  E. Kubista,et al.  Comparative analysis of two-dimensional protein patterns in malignant and normal human breast tissue. , 2001, Cancer detection and prevention.