Prof. Thomas W. Grunt, M.Sc., Ph.D.
The Signaling Networks Research Program is focusing on two cellular signaling systems, which control fundamental cellular regulatory processes such as cell differentiation, cell proliferation and programmed cell death (apoptosis). The dynamic balance between these processes is shifted in malignant tissues towards enhanced cell growth. Therefore, aberrations in signaling systems have crucial importance for malignant transformation, tumor growth and tumor progression. Clinical interest is currently focused on targeting molecular constituents that direct the activity of these signaling pathways in order to prevent and/or treat malignant diseases. Using breast and ovarian cancer models we are investigating the ErbB and the retinoid receptor signal transduction systems. ErbB proteins represent membrane receptor tyrosine kinases, whereas the retinoid receptors belong to the large superfamily of nuclear steroid/thyroid/retinoid receptors. Despite the fact that both receptor systems act via distinct molecular mechanisms, they yet control the same cell biological processes and are crucial for diagnosis, prognosis and therapy of cancer (1-3). In contrast to previous ideas, recent data suggest that ErbB and retinoid receptor signaling cascades interact at multiple molecular levels with each other. The primary goal of the Signaling Networks Research Program is to identify and characterize possible interactions between these signal transduction pathways, and to translate the obtained information into clinical use. Recently, a new focus with the investigation of fatty acid synthase (FASN) and its interaction with the ErbB membrane receptor system has been added to our portfolio. A major proportion of carcinomas overexpress FASN. Targeted inhibition of this enzyme blocks growth and causes apoptosis (programmed cell death) in cancer cells. Our studies aim to elucidate the molecular mechanisms of the interaction between both biochemical systems and to demonstrate a potential benefit of combined anti-ErbB and anti-FASN targeted cancer treatments.
The following issues are being addressed:
- Do ErbB and steroid/thyroid/retinoid signal transduction systems and FASN systems interact with each other?
- If yes, what are the molecular and cellular mechanisms of these interactions?
- How can we use these signaling cross-talks for clinical oncology?
Issue 1 can clearly be answered with yes. We could demonstrate that stimulation of the steroid/thyroid/retinoid system causes inhibition of the ErbB system (4-10) and vice versa activation of ErbB-receptors controls the function of the steroid and retinoid systems (4-6, 11, 16). Moreover, both ErbB and steroid/retinoid receptors are subject to autoregulatory mechanisms (9, 12). In addition, we were the first who demonstrated that one of the ErbB receptors (ErbB-3) can also be expressed within the cell nucleus (13). Correspondingly, a similar cross-talk could be demonstrated between ErbB and FASN.
Regarding issue 2 we can state that the identified mutual interactions between the individual signaling pathways do occur at the level of gene transcription (4-6, 8, 10). Furthermore, direct protein interactions are likely to occur between ErbB and steroid/thyroid/retinoid signaling in the cells used in these studies (4-6). Up to now, we could identify four levels of interaction: First at the expression and function of the respective receptor molecule itself, second at the downstream signal mediators, third at the level of gene transcription, and fourth at the epigenetic level (16). Correspondingly, a few signaling molecules and transcription factors could be identified that play crucial roles in the interaction between ErbB and FASN.
Work pertaining to issue 3 demonstrated that retinoid pretreatment of breast cancer cells sensitizes the cells against cytotoxic drugs. For instance, we observed a clear synergistic antiproliferative effect when all-trans retinoic acid is combined with cisplatin. This effect is at least partially caused by retinoid-mediated downregulation of the ErbB receptors (7). We could also show that ErbB inhibitors and retinoids cooperate during in vitro growth inhibition of carcinoma cells (14) and that an ErbB ligand (heregulin/neu differentiation factor) augments retinoid-induced differentiation of breast cancer cells (15). Moreover, ErbB targeting drugs can act synergistically with FASN-targeting drugs.
1. Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A, Press MF: Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244: 707-712, 1989.
2. Vollenweider-Zerargui L, Barrelet L, Wong Y, Lemarchand-Beraud T, Gomez F: The predictive value of estrogen and progesterone receptors’ concentrations on the clinical behavior of breast cancer in women. Clinical correlation on 547 patients. Cancer 57: 1171-1180, 1986.
3. Baj G, Arnulfo A, Deaglio S, Mallone R, Vigone A, Rosa M, Giana M, Villa L, Malavasi F, Surico N: Retinoids in breast cancer prevention and treatment. A review of the literature. Eur. J. Gynaecol. Oncol. 21: 411-415, 2000.
4. Grunt TW, Saceda M, Martin M.-B, Lupu R, Dittrich E, Krupitza G, Harant H, Huber H, Dittrich C: Bidirectional interactions between the estrogen receptor and the c-erbB-2 signaling pathways: heregulin inhibits estrogenic effects in breast cancer cells. Int. J. Cancer 63: 560-567, 1995.
5. Tang CK, Perez C, Grunt T, Waibel C, Cho C, Lupu R: Involvement of Heregulin-b2 in the acquisition of the hormone-independent phenotype of breast cancer cells. Cancer Res. 56: 3350-3358, 1996.
6. Saceda M, Grunt TW, Colomer R, Lippman ME, Lupu R, Martin MB: Regulation of estrogen receptor concentration and activity by an erbB/HER ligand in breast carcinoma cell lines. Endocrinology 137: 4322-4330, 1996.
7. Grunt TW, Dittrich E, Offterdinger M, Schneider SM, Dittrich C, Huber H: Effects of retinoic acid and fenretinide on the c-erbB-2 expression, growth and cisplatin sensitivity of breast cancer cells. Brit. J. Cancer 78: 79-87, 1998.
8. Offterdinger M, Schneider SM, Huber H, Grunt TW: Retinoids control the expression of c-erbB receptors in breast cancer cells. Biochem. Biophys. Res. Commun. 251: 907-913, 1998.
9. Schneider SM, Offterdinger M, Huber H, Grunt TW: Involvement of nuclear steroid/retinoid/thyroid receptors and of protein kinases in the regulation of growth and of c-erbB and retinoic acid receptor expression in MCF-7 breast cancer cells. Breast Cancer Res. Treatm. 58: 171-181, 1998.
10. Offterdinger M, Schneider SM, Huber H, Grunt TW: Expression of c-erbB-4/HER4 is regulated in T47D breast carcinoma cells by retinoids and vitamin D3. Biochem. Biophys. Res. Commun. 258: 559-564, 1999.
11. Flicker SH, Schneider S, Offterdinger M, Dittrich E, Fazeny B, Valenta R, Huber H, Dittrich C, Grunt TW: Tyrosine kinase signaling pathways control the expression of retinoic acid receptor-? in SK-BR-3 breast cancer cells. Cancer Lett. 115: 63-72, 1997.
12. Schneider SM, Offterdinger M, Huber H, Grunt TW: Activation of retinoic acid receptor a is sufficient for full induction of retinoid responses in SK-BR-3 and T47D human breast cancer cells. Cancer Res. 60: 5479-5487, 2000.
13. Offterdinger M, Schöfer C, Weipoltshammer K, Grunt TW: C-erbB-3: A nuclear protein in mammary epithelial cells. J. Cell Biol., 157, 929-939, 2002.
14. Grunt TW: Tyrphostins and Retinoids Cooperate During Inhibition of in vitro Growth of Ovarian Cancer Cells. Cancer Lett., 189, 147-156, 2003.
15. Offterdinger M, Schneider SM, Grunt TW: Heregulin and retinoids synergistically induce branching morphogenesis of breast cancer cells cultivated in 3D collagen gels. J. Cell. Physiol., 195, 260–275, 2003.
16. GRUNT,T.W., PUCKMAIR,K., TOMEK,K., KAINZ,B., GAIGER,A.: An EGF receptor inhibitor induces RAR-beta expression in breast and ovarian cancer cells. Biochem. Biophys. Res. Commun., 329, 1253-1259, 2005.
17. GRUNT,T.W., TOMEK,K., WAGNER,R., PUCKMAIR,K., KAINZ,B., RÜNZLER,D., GAIGER,A., KÖHLER,G., ZIELINSKI,C.C.: Upregulation of retinoic acid receptor-beta by the epidermal growth factor-receptor inhibitor PD153035 is not mediated by blockade of ErbB pathways. J. Cell. Physiol., 211, 803-815, 2007.
18. GRUNT,T.W., TOMEK,K., WAGNER,R., PUCKMAIR,K., ZIELINSKI,C.C.: The DNA binding EGFR inhibitor PD153035 and other DNA intercalating cytotoxic drugs reactivate the expression of the retinoic acid receptor-beta tumor suppressor gene in breast cancer cells. Differentiation, 75, 883-890, 2007.
19. GRUNT,T.W., WAGNER,R., GRUSCH, M., BERGER,W., SINGER,C.F., MARIAN,B., ZIELINSKI,C., LUPU,R.: Interaction between fatty acid synthase- and ErbB-systems in ovarian cancer cells. Biochem. Biophys. Res. Commun., 385, 454-459; 2009.