Abstract
LIM domain factors and associated cofactors are important developmental regulators in pattern formation and organogenesis. In addition, overexpression of two LIM-only factors (LMOs) causes acute lymphocytic leukemia. The more recently discovered LMO factor LMO4 is highly expressed in proliferating epithelial cells, and frequently overexpressed in breast carcinoma. Here we show that while LMO4 is expressed throughout mammary gland development, it is dramatically upregulated in mammary epithelial cells during midpregnancy. The LMO coactivator Clim2/Ldb1/NLI showed a similar expression pattern, consistent with the idea that LMO4 and Clim2 act as a complex in mammary epithelial cells. In MCF-7 cells, LMO4 transcripts were upregulated by heregulin, an activator of ErbB receptors that are known to be important in mammary gland development and breast cancer. To test the hypothesis that LMO4 plays roles in mammary gland development, we created an engrailed-LMO4 fusion protein. This fusion protein maintains the ability to interact with Clim2, but acts as a dominant repressor of both basal and activated transcription when recruited to a DNA-regulatory region. When the engrailed-LMO4 fusion protein was expressed under control of the MMTV promoter in transgenic mice, both ductular development in virgin mice and alveolar development in pregnant mice were inhibited. These results suggest that LMO4 plays a role in promoting mammary gland development.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Aguilar Z, Akita RW, Finn RS, Ramos BL, Pegram MD, Kabbinavar FF, Pietras RJ, Pisacane P, Sliwkowski MX and Slamon DJ . (1999). Oncogene, 18, 6050–6062.
Agulnick AD, Taira M, Breen JJ, Tanaka T, Dawid IB and Westphal H . (1996). Nature, 384, 270–272.
Andersen B, Weinberg WC, Rennekampff O, McEvilly RJ, Bermingham Jr JR, Hooshmand F, Vasilyev V, Hansbrough JF, Pittelkow MR, Yuspa SH and Rosenfeld MG . (1997). Genes Dev., 11, 1873–1884.
Bach I . (2000). Mech. Dev., 91, 5–17.
Bach I, Carriere C, Ostendorff HP, Andersen B and Rosenfeld MG . (1997). Genes Dev., 11, 1370–1380.
Bach I, Rodriguez-Esteban C, Carriere C, Bhushan A, Krones A, Rose DW, Glass CK, Andersen B, Izpisua Belmonte JC and Rosenfeld MG . (1999). Nat. Genet., 22, 394–399.
Bao J, Talmage DA, Role LW and Gautier J . (2000). Development, 127, 425–435.
Brisken C, Kaur S, Chavarria TE, Binart N, Sutherland RL, Weinberg RA, Kelly PA and Ormandy CJ . (1999). Dev. Biol., 210, 96–106.
Chen CM and Cepko CL . (2002). Development, 129, 5363–5375.
Dasen JS, O'Connell SM, Flynn SE, Treier M, Gleiberman AS, Szeto DP, Hooshmand F, Aggarwal AK and Rosenfeld MG . (1999). Cell, 97, 587–598.
Eccles SA . (2001). J. Mamm. Gland Biol. Neoplasia, 6, 393–406.
Grutz G, Forster A and Rabbitts TH . (1998). Oncogene, 17, 2799–2803.
Gruvberger S, Ringner M, Chen Y, Panavally S, Saal LH, Borg A, Ferno M, Peterson C and Meltzer PS . (2001). Cancer Res., 61, 5979–5984.
Guy CT, Webster MA, Schaller M, Parsons TJ, Cardiff RD and Muller WJ. . (1992). Proc. Natl. Acad. Sci. USA, 89, 10578–10582.
Han K and Manley JL . (1993). EMBO J., 12, 2723–2733.
Herblot S, Steff AM, Hugo P, Aplan PD and Hoang T . (2000). Nat. Immunol., 1, 138–144.
Hollemann T, Bellefroid E and Pieler T . (1998). Development, 125, 2425–2432.
Jones FE, Jerry DJ, Guarino BC, Andrews GC and Stern DF . (1996). Cell Growth Differ., 7, 1031–1038.
Jones FE and Stern DF . (1999). Oncogene, 18, 3481–3490.
Jones FE, Welte T, Fu XY and Stern DF . (1999). J. Cell Biol., 147, 77–88.
Jurata LW, Kenny DA and Gill GN . (1996). Proc. Natl. Acad. Sci. USA, 93, 11693–11698.
Kenny DA, Jurata LW, Saga Y and Gill GN . (1998). Proc. Natl. Acad. Sci. USA, 95, 11257–11262.
Kitsberg DI and Leder P . (1996). Oncogene, 13, 2507–2515.
Krane IM and Leder P . (1996). Oncogene, 12, 1781–1788.
Kudoh T and Dawid IB . (2001). Proc. Natl. Acad. Sci. USA, 98, 7852–7857.
Larson RC, Lavenir I, Larson TA, Baer R, Warren AJ, Wadman I, Nottage K and Rabbitts TH . (1996). EMBO J., 15, 1021–1027.
Leder A, Pattengale PK, Kuo A, Stewart TA and Leder P . (1986). Cell, 45, 485–495.
Li L, Cleary S, Mandarano MA, Long W, Birchmeier C and Jones FE . (2002). Oncogene, 21, 4900–4907.
Liu C, Morrisey EE and Whitsett JA . (2002). Am. J. Physiol. Lung Cell Mol. Physiol., 283, L468–L475.
Mead PE, Deconinck AE, Huber TL, Orkin SH and Zon LI . (2001). Development, 128, 2301–2308.
Montross WT, Ji H and McCrea PD . (2000). J. Cell Sci., 113, 1759–1770.
Muller WJ, Sinn E, Pattengale PK, Wallace R and Leder P . (1988). Cell, 54, 105–115.
Ono Y, Fukuhara N and Yoshie O . (1998). Mol. Cell. Biol., 18, 6939–6950.
Osada H, Grutz G, Axelson H, Forster A and Rabbitts TH . (1995). Proc. Natl. Acad. Sci. USA, 92, 9585–9589.
Osada H, Grutz GG, Axelson H, Forster A and Rabbitts TH . (1997). Leukemia, 11 (Suppl 3), 307–312.
Rabbitts TH, Bucher K, Chung G, Grutz G, Warren A and Yamada Y . (1999). Cancer Res., 59, 1794s–1798s.
Racevskis J, Dill A, Sparano JA and Ruan H . (1999). Biochim. Biophys. Acta, 1445, 148–153.
Rudland PS, Barraclough R, Fernig DG and Smith JA . (1998). Biochem. Soc. Symp., 63, 1–20.
Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A and Press MF . (1989). Science, 244, 707–712.
Stern DF . (2003). Exp. Cell Res., 284, 89–98.
Sugihara TM, Bach I, Kioussi C, Rosenfeld MG and Andersen B . (1998). Proc. Natl. Acad. Sci. USA, 95, 15418–15423.
Sugihara TM, Kudryavtseva EI, Kumar V, Horridge JJ and Andersen B . (2001). J. Biol. Chem., 276, 33036–33044.
Sum EY, Peng B, Yu X, Chen J, Byrne J, Lindeman GJ and Visvader JE . (2002). J. Biol. Chem., 277, 7849–7856.
Sykes TG, Rodaway AR, Walmsley ME and Patient RK . (1998). Development, 125, 4595–4605.
Taylor D, Badiani P and Weston K . (1996). Genes Dev., 10, 2732–2744.
Valge-Archer VE, Osada H, Warren AJ, Forster A, Li J, Baer R and Rabbitts TH . (1994). Proc. Natl. Acad. Sci. USA, 91, 8617–8621.
Visvader JE, Mao X, Fujiwara Y, Hahm K and Orkin SH . (1997). Proc. Natl. Acad. Sci. USA, 94, 13707–13712.
Visvader JE, Venter D, Hahm K, Santamaria M, Sum EY, O'Reilly L, White D, Williams R, Armes J and Lindeman GJ . (2001). Proc. Natl. Acad. Sci. USA, 98, 14452–14457.
Wadman I, Li J, Bash RO, Forster A, Osada H, Rabbitts TH and Baer R . (1994). EMBO J., 13, 4831–4839.
Wadman IA, Osada H, Grutz GG, Agulnick AD, Westphal H, Forster A and Rabbitts TH . (1997). EMBO J., 16, 3145–3157.
Yang Y, Spitzer E, Meyer D, Sachs M, Niemann C, Hartmann G, Weidner KM, Birchmeier C and Birchmeier W . (1995). J. Cell Biol., 131, 215–226.
Zeng C, Justice NJ, Abdelilah S, Chan YM, Jan LY and Jan YN . (1998). Proc. Natl. Acad. Sci. USA, 95, 10637–10642.
Acknowledgements
We thank Philip Leder for the MMTV plasmid; Ingolf Bach for Clim antisera; Jane Visvader for LMO4 antibody; Gordon Gill and Geof Rosenfeld for suggestions; and Taosheng Huang, Kristen Jepsen, and Steven M Lipkin for reading the manuscript. This work was supported by the NIH award AR02080, the Department of the Army award DAMD17-00-1-0182, the California Breast Cancer Research Program award 5JB-0119 (to BA.), and the Department of the Army award DAMD17-01-1-0183 (to NW).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Wang, N., Kudryavtseva, E., Ch'en, I. et al. Expression of an engrailed-LMO4 fusion protein in mammary epithelial cells inhibits mammary gland development in mice. Oncogene 23, 1507–1513 (2004). https://doi.org/10.1038/sj.onc.1207288
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1207288
Keywords
This article is cited by
-
The LIM-domain only protein 4 contributes to lung epithelial cell proliferation but is not essential for tumor progression
Respiratory Research (2015)
-
LIM-domain-only proteins: multifunctional nuclear transcription coregulators that interacts with diverse proteins
Molecular Biology Reports (2014)
-
LIM-domain-only proteins in cancer
Nature Reviews Cancer (2013)
-
Repression of Lim only protein 4-activated transcription inhibits proliferation and induces apoptosis of normal mammary epithelial cells and breast cancer cells
Clinical & Experimental Metastasis (2010)
-
LMO4 is an essential mediator of ErbB2/HER2/Neu-induced breast cancer cell cycle progression
Oncogene (2009)