Hormones and Cancer

Interaction between stress hormones and breast cancer. Study of new therapeutic options. Role of adrenergic receptors in different stages of tumor progression.

Hormones and Cancer

  • Isabel Alicia Lüthy Currículum Vitae

    Ph.D., 1983, Faculty of Exact and Natural Sciences, , Universidad de Buenos Aires.

    Principal Investigator, CONICET

  • Hormones and Cancer

    Dra. Ariana Bruzzone (Asistant Investigator CONICET)

    Dra. Liliana Dain (Staff Profesional Investigador, Centro Nacional de Genética, ANLIS)

    Lic. Ezequiel M. Rivero (Fellow Type I, CONICET)

    Lic. Lucía Gargiulo (Fellow ANPCYT)

    Lic. Carlos David Bruque (Fellow ANLIS_MINCYT)

Breast cancer is the most frequent malignancy in women. In Argentina, approximately 5,400 women die each year and there is an estimation of 17,000 new cases is diagnosed. Even if the existing therapies for breast cancer caused a great progress in the treatment of this disease, significantly improving the survival, in a great proportion of patients, mainly in those with recurrence or metas­ta­sis, resistance to the treatment sometimes appear. For this reason it is of clinical importance to find other treatments with different mechanism of action in order to complement the existent therapies.

Stressing experiences induce noradrenaline and adrenaline release. These stress hormones bind to 9 adrenoceptors, which are divided in three main types, alpha1, alpha2 and beta-adrenceptors. Adrenoceptors belong to the superfamily of seven trans-­mem­bra­­ne domain-receptors cou­ple­d to G proteins (GPCRs).

Our group has been working during the last years in the characterization of alpha2-adrenoceptors and in their effects on different experimental models of breast cancer. The main objective of this work is to contribute to the knowledge of the influence of these receptors on tumor progression and thus contribute to improve patient´s life quality.

In the first place, we have investigated the adrenergic action on human breast cancer MCF-7 cells and found that the endogenous catecholamines, adrenaline and noradrenaline significantly stimulate cell proliferation. The pharmacologic analysis of this action, lend us to propose that the action was mediated by alpha2-adrenoceptors. We then described the alpha2-adrenoceptors in several human breast cancer cell lines, as well as in non-cancer cell lines. In every cell line the alpha2-adrenergic agonists increased cell proliferation.

We have afterwards demonstrated that the alpha2-adrenergic compounds increase tumor growth in two independent experimental models of breast cancer. The alpha2-adrenergic antagonist rauwolscine when administered alone, always significantly decreased tumor growth, behaving as an inverse agonist. We have also described by im­mu­­no­cytochemistry and immuno­histochemistry that the normal murine fibroblasts and those associated to tumors (CAFs) expressed alpha2-adrenoceptors.

We have also found that β-adrenoceptors are associated with an inhibition of cell proliferation in human breast cancer cells and this effect was also observed in the same experimental models in animals.

As a whole, this work demonstrates that alpha2-adrenoceptors are expressed in breast tumors, both human and murine, and that their activation is associated to an increase of cell proliferation and tumor growth. The alpha2-adrenergic antagonist rauwolscine always reversed the proliferative effect of the agonists, and more relevant, in the absence of agonists it inhibited cell proliferation and tumor growth when compared to the control, suggesting the possibility of using it as a complementary therapy for breast cancer. The beta-adrenoceptors on the other hand, are associated to an inhibition of cell proliferation and tumor growth. 

  1. Five novel hormone responsive cell lines derived from murine mammary ductal carcinomas. In vivo and in vitro effects of estrogen and progestins. Lanari, C., Lüthy, I.A. , Lamb, C.A., Fabris, V., Pagano, E., Helguero, L., Sanjuan, N., Merani, S., Molinolo, A.A. Cancer Research 61: 293-302, 2001.
  2. Androgen receptors in human melanoma cell lines IIB-MEL-LES and IIB-MEL-IAN and in human melanoma metastases. Morvillo, V., Lüthy, I.A. , Bravo, A.I., Capurro, M.I., Portela, P., Calandra, R.S., Mordoh, J. Melanoma Research 12 (6): 529-38, 2002.
  3. Augmented serum levels of the IGF-I/IGFBP3 ratio in pre-menopausal patients with ty­pe I breast cysts. Enriori, P., Fischer, C., Go­ri, J., Etkin, A., Ca­lan­dra R.S., Lüthy, I.A . European Journal of Endocrinology 148 (2): 177-184, 2003.
  4. Three Novel Hormone-Responsive Cell Lines Derived from Primary Human Breast Carcino­mas. Functional Characterization. Vázquez, S. M., Mladovan, A. G., Garbovesky, C., Baldi, A., Lüthy, I. A . Journal of Cellular Physiology 199 (3): 460-469, 2004.
  5. Breast cyst fluids in­crease proliferation of breast cell lines in correlation with their content of hormones and growth factors. Enriori, P., Vázquez, S.M., Chiauzzi, V., Pérez, C., Fischer, C.R., Go­ri, J.R., Etkin, A.E., Charreau, E. H., Calandra R.S., Lüthy, I.A. Clinical Endocrinology 64(1): 20-28, 2006.
  6. Human breast cell lines exhibit functional a 2 -Adrenergic Receptors. Vázquez, S. M., Mladovan, A. G., Pérez, C., Bruzzone, A., Baldi, A., Lüthy, I. A . Cancer Chemotherapy and Pharmacology 58: 50-61, 2006 .
  7. Contribution of alpha2-adrenoceptors to the mitogenic effect of catecholestrogen in human breast cancer MCF-7 cells. Chiesa IJ, Castillo LF, Lüthy IA. Journal of Steroid Biochemistry and Molecular Biology 110 (1-2): 170-185, 2008. 
  8. Alpha2-Adrenergic action on cell proliferation and mammary tumour growth in mice. Bruzzone A, Pérez Piñero C, Castillo LF, Sarappa MG, Rojas P, Lanari C, Lüthy IA. British Journal of Pharmacology 155 (4): 494-504, 2008. 
  9. Novel Human Breast Cancer Cell Lines IBH-4, IBH-6 and IBH-7 Growing in Nude Mice. Bruzzone A, Vanzulli S, Soldati R, Giulianelli S, Lanari C, Lüthy IA.Journal of Cellular Physiology 219: 477- 484, 2009. 
  10. Adrenoceptors: Non Conventional Target for Breast Cancer? Lüthy IA, Bruzzone A, Pérez Piñero C, Chiesa I, Castillo L, Vázquez SM. (Review solicitado por la revista). Current Medicinal Che­mis­try 16 (15): 1850-62, 2009. 
  11. Might adrenergic alpha2C-agonists/alpha2A-antagonists become novel therapeutic tools for pain treatment with morphine? Cardinaletti C, Mattioli L, Ghelfi F, Del Bello F, Giannella M, Bruzzone A, Paris H, Perfumi M, Piergentili A, Quaglia W, Pigini M. J Med Chem Nov 26;52(22):7319-22, 2009. 
  12. Expression analysis of Epithelial Cadherin and related Proteins in IBH-6 and IBH-4 Human Breast Cancer Cell Lines. Lapyckyj L, Castillo LF, Matos ML, Gabrielli NM, Lüthy IA, Vazquez-Levin MH. Journal of Cellular Physiology 222: 596-605, 2010. 
  13. Classical and non-classical membrane progesterone receptorsin murine mammary carcinomas: Agonistic effects of progestins and antiprogestins mediating rapid non-genomic effects. Bottino M, Rojas P, Soldati R, Mondillo C, Pignataro O, Calvo J, Gutkind JS, Amornphimoltham P, Molinolo A, Lüthy I, Lanari C. Breast Cancer Research and Treatment 126: 621–636, 2011.
  14. α2-adrenoceptors enhance cell proliferation and mammary tumor growth acting through both the stroma and the tumor cells. A. Bruzzone*, C. Pérez Piñero*, P. Rojas, M. Romanato, H. Gass, C. Lanari, I.A. Lüthy. *Same participation in the work. Current Cancer Drug Targets 11:763-774, 2011. 
  15. Adrenergic action in breast cancer. IA Lüthy, A Bruzzone, C Pérez Piñero. Current Cancer Therapy Reviews 8: 90-99, 2012. (Review solicitado por los editores del volumen especial: “The adrenergic axis in Cancer”).
  16. Involvement of alpha2- and beta2-adreno­cep­tors on breast cancer cell proliferation and tumour growth regulation”, C. Pérez Piñero, A. Bruzzone, M.G. Sarappa, L.F. Castillo, I.A. Lüthy. British Journal of Pharmacology 166 (2): 721-736, 2012.
  17. PI3K/AKT pathway regulates the ligand-independent activation of steroid receptors, hormone independence and tumor differentiation in breast cancer. M Riggio, ML Polo, M Blaustein, A Colman Lerner, I Lüthy, C Lanari, V Novaro. Carcinogenesis 33 (3): 509-518, 2012.
  18. Human adipose tissue from normal and tumoral breast regulates the behavior of mammary epithelial cells. Pistone Creydt V, Fletcher S, Giudice J, Bruzzone A,Chasseing N, Gonzalez E, Sacca P, Calvo J. Clinical and Translational Oncology 15(2):124-31, 2013.
  19. Dosage-dependent regulation of cell proliferation and adhesion through dual Beta2-adrenergic receptor/cAMP signals. Bruzzone A, Saulière A, Finana F, Sénard J-M, Lüthy, I*, Galés C.*. *Same participation in the work. FASEB Journal 28, 000–000 (2014).

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