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MFG-E8/lactadherin regulates cyclins D1/D3 expression and enhances the tumorigenic potential of mammary epithelial cells

Oncogene volume 31, pages 1521–1532 (2012)Cite this article

Abstract

Milk fat globule-EGF factor 8 (MFG-E8) is a glycoprotein highly expressed in breast cancer that contributes to tumor progression through largely undefined mechanisms. By analyzing publicly available gene expression profiles of breast carcinomas, we found that MFG-E8 is highly expressed in primary and metastatic breast carcinomas, associated with absent estrogen receptor expression. Immunohistochemistry analysis of breast cancer biopsies revealed that MFG-E8 is expressed on the cell membrane as well as in the cytoplasm and nucleus. We also show that increased expression of MFG-E8 in mammary carcinoma cells increases their tumorigenicity in immunodeficient mice, and conversely, its downregulation reduces their in vivo growth. Moreover, expression of MFG-E8 in immortalized mammary epithelial cells promotes their growth and branching in three-dimensional collagen matrices and induces the expression of cyclins D1/D3 and N-cadherin. A mutant protein unable to bind integrins can in part exert these effects, indicating that MFG-E8 function is only partially dependent on integrin activation. We conclude that MFG-E8-dependent signaling stimulates cell proliferation and the acquisition of mesenchymal properties and contributes to mammary carcinoma development.

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References

  • Andersen MH, Berglund L, Rasmussen JT, Petersen TE . (1997). Bovine PAS-6/7 binds alpha v beta 5 integrins and anionic phospholipids through two domains. Biochemistry 36: 5441–5446.

    Article  CAS  PubMed  Google Scholar 

  • Aslakson CJ, Miller FR . (1992). Selective events in the metastatic process defined by analysis of the sequential dissemination of subpopulations of a mouse mammary tumor. Cancer Res 52: 1399–1405.

    CAS  PubMed  Google Scholar 

  • Atabai K, Fernandez R, Huang X, Ueki I, Kline A, Li Y et al. (2005). Mfge8 is critical for mammary gland remodeling during involution. Mol Biol Cell 16: 5528–5537.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ayers M, Symmans WF, Stec J, Damokosh AI, Clark E, Hess K et al. (2004). Gene expression profiles predict complete pathologic response to neoadjuvant paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide chemotherapy in breast cancer. J Clin Oncol 22: 2284–2293.

    Article  CAS  PubMed  Google Scholar 

  • Ceriani RL, Blank EW, Peterson JA . (1987). Experimental immunotherapy of human breast carcinomas implanted in nude mice with a mixture of monoclonal antibodies against human milk fat globule components. Cancer Res 47: 532–540.

    CAS  PubMed  Google Scholar 

  • Ceriani RL, Sasaki M, Sussman H, Wara WM, Blank EW . (1982). Circulating human mammary epithelial antigens in breast cancer. Proc Natl Acad Sci USA 79: 5420–5424.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ceriani RL, Thompson K, Peterson JA, Abraham S . (1977). Surface differentiation antigens of human mammary epithelial cells carried on the human milk fat globule. Proc Natl Acad Sci USA 74: 582–586.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cowin P, Rowlands TM, Hatsell SJ . (2005). Cadherins and catenins in breast cancer. Curr Opin Cell Biol 17: 499–508.

    Article  CAS  PubMed  Google Scholar 

  • Ensslin MA, Shur BD . (2007). The EGF repeat and discoidin domain protein, SED1/MFG-E8, is required for mammary gland branching morphogenesis. Proc Natl Acad Sci USA 104: 2715–2720.

    Article  PubMed  PubMed Central  Google Scholar 

  • Hanayama R, Nagata S . (2005). Impaired involution of mammary glands in the absence of milk fat globule EGF factor 8. Proc Natl Acad Sci U S A 102: 16886–16891.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hanayama R, Tanaka M, Miwa K, Shinohara A, Iwamatsu A, Nagata S . (2002). Identification of a factor that links apoptotic cells to phagocytes. Nature 417: 182–187.

    Article  CAS  PubMed  Google Scholar 

  • Hanayama R, Tanaka M, Miyasaka K, Aozasa K, Koike M, Uchiyama Y et al. (2004). Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-deficient mice. Science 304: 1147–1150.

    Article  CAS  PubMed  Google Scholar 

  • Hazan RB, Phillips GR, Qiao RF, Norton L, Aaronson SA . (2000). Exogenous expression of N-cadherin in breast cancer cells induces cell migration, invasion, and metastasis. J Cell Biol 148: 779–790.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hess KR, Anderson K, Symmans WF, Valero V, Ibrahim N, Mejia JA et al. (2006). Pharmacogenomic predictor of sensitivity to preoperative chemotherapy with paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide in breast cancer. J Clin Oncol 24: 4236–4244.

    Article  CAS  PubMed  Google Scholar 

  • Janda E, Lehmann K, Killisch I, Jechlinger M, Herzig M, Downward J et al. (2002). Ras and TGF[beta] cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. J Cell Biol 156: 299–313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jinushi M, Nakazaki Y, Carrasco DR, Draganov D, Souders N, Johnson M et al. (2008). Milk fat globule EGF-8 promotes melanoma progression through coordinated Akt and twist signaling in the tumor microenvironment. Cancer Res 68: 8889–8898.

    Article  CAS  PubMed  Google Scholar 

  • Jinushi M, Sato M, Kanamoto A, Itoh A, Nagai S, Koyasu S et al. (2009). Milk fat globule epidermal growth factor-8 blockade triggers tumor destruction through coordinated cell-autonomous and immune-mediated mechanisms. J Exp Med 206: 1317–1326.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Joel PB, Traish AM, Lannigan DA . (1998). Estradiol-induced phosphorylation of serine 118 in the estrogen receptor is independent of p42/p44 mitogen-activated protein kinase. J Biol Chem 273: 13317–13323.

    Article  CAS  PubMed  Google Scholar 

  • Larocca D, Peterson JA, Urrea R, Kuniyoshi J, Bistrain AM, Ceriani RL . (1991). A Mr 46 000 human milk fat globule protein that is highly expressed in human breast tumors contains factor VIII-like domains. Cancer Res 51: 4994–4998.

    CAS  PubMed  Google Scholar 

  • Lee MH, Yang HY . (2003). Regulators of G1 cyclin-dependent kinases and cancers. Cancer Metast Rev 22: 435–449.

    Article  CAS  Google Scholar 

  • Lincoln II DW, Phillips PG, Bove K . (2003). Estrogen-induced Ets-1 promotes capillary formation in an in vitro tumor angiogenesis model. Breast Cancer Res Treat 78: 167–178.

    Article  CAS  PubMed  Google Scholar 

  • Loi S, Haibe-Kains B, Desmedt C, Lallemand F, Tutt AM, Gillet C et al. (2007). Definition of clinically distinct molecular subtypes in estrogen receptor-positive breast carcinomas through genomic grade. J Clin Oncol 25: 1239–1246.

    Article  CAS  PubMed  Google Scholar 

  • Miller LD, Smeds J, George J, Vega VB, Vergara L, Ploner A et al. (2005). An expression signature for p53 status in human breast cancer predicts mutation status, transcriptional effects, and patient survival. Proc Natl Acad Sci USA 102: 13550–13555.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nagi C, Guttman M, Jaffer S, Qiao R, Keren R, Triana A et al. (2005). N-cadherin expression in breast cancer: correlation with an aggressive histologic variant—invasive micropapillary carcinoma. Breast Cancer Res Treat 94: 225–235.

    Article  CAS  PubMed  Google Scholar 

  • Neutzner M, Lopez T, Feng X, Bergmann-Leitner ES, Leitner WW, Udey MC . (2007). MFG-E8/lactadherin promotes tumor growth in an angiogenesis-dependent transgenic mouse model of multistage carcinogenesis. Cancer Res 67: 6777–6785.

    Article  CAS  PubMed  Google Scholar 

  • Oft M, Peli J, Rudaz C, Schwarz H, Beug H, Reichmann E . (1996). TGF-beta1 and Ha-Ras collaborate in modulating the phenotypic plasticity and invasiveness of epithelial tumor cells. Genes Dev 10: 2462–2477.

    Article  CAS  PubMed  Google Scholar 

  • Oshima K, Aoki N, Negi M, Kishi M, Kitajima K, Matsuda T . (1999). Lactation-dependent expression of an mRNA splice variant with an exon for a multiply O-glycosylated domain of mouse milk fat globule glycoprotein MFG-E8. Biochem Biophys Res Commun 254: 522–528.

    Article  CAS  PubMed  Google Scholar 

  • Peintinger F, Anderson K, Mazouni C, Kuerer HM, Hatzis C, Lin F et al. (2007). Thirty-gene pharmacogenomic test correlates with residual cancer burden after preoperative chemotherapy for breast cancer. Clin Cancer Res 13: 4078–4082.

    Article  CAS  PubMed  Google Scholar 

  • Peterson JA, Zava DT, Duwe AK, Blank EW, Battifora H, Ceriani RL . (1990). Biochemical and histological characterization of antigens preferentially expressed on the surface and cytoplasm of breast carcinoma cells identified by monoclonal antibodies against the human milk fat globule. Hybridoma 9: 221–235.

    Article  CAS  PubMed  Google Scholar 

  • Raymond A, Ensslin MA, Shur BD . (2009). SED1/MFG-E8: a bi-motif protein that orchestrates diverse cellular interactions. J Cell Biochem 106: 957–966.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Roy PG, Thompson AM . (2006). Cyclin D1 and breast cancer. Breast 15: 718–727.

    Article  PubMed  Google Scholar 

  • Russell A, Thompson MA, Hendley J, Trute L, Armes J, Germain D . (1999). Cyclin D1 and D3 associate with the SCF complex and are coordinately elevated in breast cancer. Oncogene 18: 1983–1991.

    Article  CAS  PubMed  Google Scholar 

  • Silvestre JS, Thery C, Hamard G, Boddaert J, Aguilar B, Delcayre A et al. (2005). Lactadherin promotes VEGF-dependent neovascularization. Nat Med 11: 499–506.

    Article  CAS  PubMed  Google Scholar 

  • Suyama K, Shapiro I, Guttman M, Hazan RB . (2002). A signaling pathway leading to metastasis is controlled by N-cadherin and the FGF receptor. Cancer Cell 2: 301–314.

    Article  CAS  PubMed  Google Scholar 

  • Symmans WF, Ayers M, Clark EA, Stec J, Hess KR, Sneige N et al. (2003). Total RNA yield and microarray gene expression profiles from fine-needle aspiration biopsy and core-needle biopsy samples of breast carcinoma. Cancer 97: 2960–2971.

    Article  CAS  PubMed  Google Scholar 

  • Taubenberger AV, Woodruff MA, Bai H, Muller DJ, Hutmacher DW . (2010). The effect of unlocking RGD-motifs in collagen I on pre-osteoblast adhesion and differentiation. Biomaterials 31: 2827–2835.

    Article  CAS  PubMed  Google Scholar 

  • Taylor MR, Couto JR, Scallan CD, Ceriani RL, Peterson JA . (1997). Lactadherin (formerly BA46), a membrane-associated glycoprotein expressed in human milk and breast carcinomas, promotes Arg-Gly-Asp (RGD)-dependent cell adhesion. DNA Cell Biol 16: 861–869.

    Article  CAS  PubMed  Google Scholar 

  • Wang TC, Cardiff RD, Zukerberg L, Lees E, Arnold A, Schmidt EV . (1994). Mammary hyperplasia and carcinoma in MMTV-cyclin D1 transgenic mice. Nature 369: 669–671.

    Article  CAS  PubMed  Google Scholar 

  • Yang C, Hayashida T, Forster N, Li C, Shen D, Maheswaran S et al. (2011). The integrin alpha(v)beta(3–5) ligand MFG-E8 is a p63/p73 target gene in triple-negative breast cancers but exhibits suppressive functions in ER(+) and erbB2(+) breast cancers. Cancer Res 71: 937–945.

    Article  CAS  PubMed  Google Scholar 

  • Yu Q, Geng Y, Sicinski P . (2001). Specific protection against breast cancers by cyclin D1 ablation. Nature 411: 1017–1021.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by a grant from the MEDIC Foundation to AM. We thank J-C Stehle and J Horlbeck of the UNIL Mouse Pathology facility for help with immunohistochemistry, F Botta for help in obtaining the breast carcinoma biopsies, C Brisken for reagents and T Petrova for discussions and support.

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Authors and Affiliations

  1. Division of Experimental Oncology, Centre Pluridisciplinaire d’Oncologie, Lausanne Cancer Center, University of Lausanne, Epalinges, Switzerland

    C Carrascosa, R G Obula & A Mariotti

  2. Swiss Institute of Bioinformatics, University of Lausanne, Lausanne, Switzerland

    E Missiaglia & M Delorenzi

  3. Institute of Pathology, CHUV, Lausanne, Switzerland

    H-A Lehr

  4. Département de Formation et Recherche, CHUV, University of Lausanne, Lausanne, Switzerland

    M Delorenzi & A Mariotti

  5. Laboratory of Molecular Diagnostics, Institute of Pathology, Locarno, Switzerland

    M Frattini

  6. Department of Medicine, University of Fribourg, Fribourg, Switzerland

    C Rüegg

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  1. C Carrascosa
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  2. R G Obula
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Correspondence to A Mariotti.

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Carrascosa, C., Obula, R., Missiaglia, E. et al. MFG-E8/lactadherin regulates cyclins D1/D3 expression and enhances the tumorigenic potential of mammary epithelial cells. Oncogene 31, 1521–1532 (2012). https://doi.org/10.1038/onc.2011.356

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