Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Interactions between progestins and heregulin (HRG) signaling pathways: HRG acts as mediator of progestins proliferative effects in mouse mammary adenocarcinomas

Oncogene volume 18, pages 6370–6379 (1999)Cite this article

Abstract

The present study addressed links between progestin and heregulin (HRG) signaling pathways in mammary tumors. An experimental model of hormonal carcinogenesis, in which the synthetic progestin medroxyprogesterone acetate (MPA) induced mammary adenocarcinomas in female Balb/c mice, was used. MPA induced an in vivo up-regulation of HRG mRNA expression in progestin-dependent (HD) tumor lines. Mammary tumor progression to a progestin-independent (HI) phenotype was accompanied by a high constitutive expression of HRG. The HRG message arose from the tumor epithelial cells. Primary cultures of malignant epithelial cells from a HD tumor line were used to investigate HRG involvement on cell proliferation. HRG induced a potent proliferative effect on these cells and potentiated MPA mitogenic effects. Blocking endogenous HRG synthesis by antisense oligodeoxynucleotides (ASODNs) to HRG mRNA inhibited MPA-induced cell growth, indicating that HRG acts as a mediator of MPA-induced growth. High levels of ErbB-2 and ErbB-3 expression and low ErbB-4 levels were found in HD cells. Treatment of these cells with either MPA or HRG resulted in tyrosine phosphorylation of both ErbB-2 and ErbB-3. Furthermore, both HRG and MPA proliferative effects were abolished when cells were treated with ASODNs to ErbB-2 mRNA, providing evidence for a critical role of ErbB-2 in HRG-induced growth. Finally, blocking type I insulin-like growth factor receptor (IGF-IR) expression with ASODN resulted in the complete inhibition of HRG proliferative effect, demonstrating that a functional IGF-IR is required for HRG mitogenic activity. These results provide the first evidence of interactions between progestins and HRB/ErbB signal transduction pathways in mammary cancer and the first demonstration that IGF-IR is required for HRG proliferative effects.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  • Amundadottir LT and Leder P. . 1998 Oncogene 16: 737–746.

  • Backer JM, Myers MG, Sun XJ, Chen DJ, Schoelson SE, Mivalpeix M and White MF. . 1993 J. Biol. Chem. 268: 8204–8212.

  • Bacus SS, Gudkov AV, Zelnick CR, Chin D, Stern R, Stancovski H, Peles E, Ben-Baruch N, Farbstein H, Lupu R, Wen D, Sela M and Yarden Y. . 1993 Cancer Res. 53: 5251–5261.

  • Barone MV and Courtneidge SA. . 1995 Nature 378: 509–512.

  • Berlii R, Graus Porta D, Woods-Cook K, Chen X, Yarden Y and Hynes NE. . 1995 Mol. Cell. Biol. 15: 6496–6505.

  • Carraway KL and Cantley LC. . 1994 Cell 78: 5–8.

  • Chomczysnki P and Sacchi N. . 1987 Anal. Biochem. 162: 156–159.

  • Colomer R, Lupu R, Bacus SS and Gelmann EP. . 1994 Br. J. Cancer 70: 819–825.

  • Coppola D, Ferber A, Masahiko M, Sell C, D'Ambrosio C, Rubin R and Baserga R. . 1994 Mol. Cell. Biol. 14: 4588–4595.

  • Culouscou JM, Plowman GD, Carlton GW, Green JM and Shoyab M. . 1993 J. Biol. Chem. 268: 18407–18410.

  • Dran G, Luthy IA, Molinolo AA, Montecchia F, Charreau EH, Dosne Pasqualini C and Lanari C. . 1995 Breast Cancer Res. Treat. 35: 173–186.

  • Elizalde PV, Lanari C, Molinolo AA, Guerra FK, Balañá ME, Simian M, Iribarren AM, Charreau EH. . 1998 J. Steroid Biochem. Mol. Biol. 67: 305–317.

  • Fedi P, Pierce J, Di Fiore PP and Kraus M. . 1994 Mol. Cell. Biol. 14: 492–500.

  • Graus-Porta D, Beerli RR and Hynes NE. . 1995 Mol. Cell. Biol. 15: 1182–1191.

  • Graus-Porta D, Beerli RR, Daly JM and Hynes NE. . 1997 EMBO J. 16: 1647–1655.

  • Grunt TW, Saceda M, Martin MB, Lupu R, Dittrich E, Krupitza G, Harant H, Huber H and Dittrich C. . 1995 Int. J. Cancer 63: 560–567.

  • Guerra FK, Eijan AM, Puricelli L, Alonso DF, Bal de Kier Joffé E, Kornblihtt AR, Charreau EH and Elizalde PV. . 1996 Int. J. Cancer 65: 812–820.

  • Hamburger AW and Yoo JY. . 1997 Mol. Cell. Endocrinol. 138: 163–171.

  • Holmes WE, Sliwkowski MX, Akita RW, Henzel WJ, Lee J, Park JW, Yansura D, Abadi N, Raab H, Lewis GD, Shepard M, Wood WI, Goeddel DV and Vandlen RL. . 1992 Science 256: 1205–1210.

  • Krane IM and Leder P. . 1996 Oncogene 12: 1781–1788.

  • Lanari C, Kordon E, Molinolo AA, Dosne Pasqualini C and Charrau EH. . 1989 Int. J. Cancer 43: 845–850.

  • Lewis GD, Lofgren JA, McMurtrey AE, Nuijens A, Fendly BM, Bauer KD and Sliwkowski MX. . 1996 Cancer Res. 56: 1457–1465.

  • Lowe WL, Fu R and Banko M. . 1997 Endocrinology 138: 2219–2226.

  • Lupu R and Lippman ME. . 1993 Breast Cancer Res. Treat. 27: 83–93.

  • Marte BM, Graus-Porta D, Jeschke M, Fabbro D, Hynes NE and Taverna D. . 1995a Oncogene 10: 167–175.

  • Marte BB, Jeschke M, Graus-Porta D, Taverna D, Hofer P, Groner B, Yarden Y and Hynes N. . 1995b Mol. Endocrinol. 9: 14–23.

  • Molinolo AA, Lanari C, Charreau EH, San Juan N and Dosne Pasqualini C. . 1987 J. Natl. Cancer Inst. 79: 1341–1350.

  • Normanno N, Kim N, Wen D, Smith K, Harris AL, Plowman G, Colletta G, Ciardello F and Salomon D. . 1995 Breast Cancer Res. Treat. 35: 293–297.

  • Normanno N, Qi C, Gullik WJ, Persico MG, Yarden Y, Wen D, Plowman GD, Kenney N, Johnson GR, Kim N, Brandt R, Martinez-Lacaci I, Dickson RB and Salomon DS. . 1993 Int. J. Oncol. 2: 903–911.

  • Peles E and Yarden Y. . 1993 BioEssays 15: 815–824.

  • Peles E, Bacus SS, Koski RA, Lu HS, Wen D, Odgen SG, Ben Levy R and Yarden Y. . 1992 Cell 69: 205–216.

  • Pietras RJ, Arboleda J, Reese DM, Wongpivat N, Pegram MD, Ramos L, Gorman CM, Parker M, Sliwkowski MX and Slamon D. . 1995 Oncogene 10: 2435–2446.

  • Pinkas-Kramarski R, Alroy I and Yarden Y. . 1997 J. Mam. Gland Biol. Neoplasia 2: 97–107.

  • Ram TG, Kokeny KE, Dilts CA and Ethier SP. . 1995 J. Cell. Physiol. 163: 589–596.

  • Saceda M, Grunt TW, Colomer R, Lippman ME, Lupu R and Martin MB. . 1996 Endocrinology 137: 4322–4330.

  • Scatchard G. . 1949 Ann. NY Acad. Sci. 51: 660–672.

  • Sell C, Dumenil G, Deveaud C, Miura M, Coppola D, De Angelis T, Rubin R, Efstratiadis A and Baserga R. . 1994 Mol. Cell. Biol. 14: 3604–3612.

  • Sepp-Lorenzino L, Eberhard I, Ma Z, Cho C, Serve H, Liu F, Rosen N and Lupu R. . 1996 Oncogene 12: 1679–1687.

  • Tang C, Perez C, Grunt T, Waibel C, Cho C and Lupu R. . 1996 Cancer Res. 56: 3350–3358.

  • Wen D, Suggs V, Karunagaran D, Liyu R, Cupples L, Luo Y, Jansen AM, Ben Barush N, Trolinger DB, Jacobson VL, Meng T, Lu HS, Hu S, Chang D, Yanigahara D, Koski RA and Yarden Y. . 1994 Mol. Cell. Biol. 14: 1909–1919.

  • Wen D, Peles E, Cupples R, Suggs SV, Bacus SS, Luo Y, Trail G, Hu S, Silbiger SM, Ben Levy R, Koski RA, Lu HS and Yarden Y. . 1992 Cell 69: 559–572.

  • Yang Y, Spitzer E, Meyer D, Sachs M, Niemann C, Hartmann G, Weidner KM, Birchmeier C and Birchmeier WJ. . 1995 J. Cell. Biol. 131: 215–226.

  • Young JAT and Trowsdale J. . 1985 Nucl. Acids Res. 13: 8883–8891.

Download references

Acknowledgements

The authors thank Dr C Lanari for providing the tumors and for advice with primary cultures assays, Dr AM Iribarren for help with the HRG ASODN design, Dr E Bal de Kier Joffé for critical discussion and review of the work and Dr C Dosne Pasqualini for review of the manuscript. This work was supported by grants from the National Scientific Council of Argentina, CONICET.

Author information

Authors and Affiliations

  1. Instituto de Biología y Medicina Experimental (IBYME), Buenos Aires 1428, 2490, Obligado, Argentina

    Maria Eugenia Balañá, Leticia Labriola, Eduardo H Charreau & Patricia V Elizalde

  2. Lawrence Berkeley National Laboratories, University of California Berkeley, 1 Cyclotron Road, Building 934 Berkeley, California, 94710, CA, USA

    Ruth Lupu

Authors
  1. Maria Eugenia Balañá
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ruth Lupu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Leticia Labriola
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eduardo H Charreau
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Patricia V Elizalde
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Balañá, M., Lupu, R., Labriola, L. et al. Interactions between progestins and heregulin (HRG) signaling pathways: HRG acts as mediator of progestins proliferative effects in mouse mammary adenocarcinomas. Oncogene 18, 6370–6379 (1999). https://doi.org/10.1038/sj.onc.1203028

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1203028

Keywords

This article is cited by

Search

Advanced search

Quick links