Hormones and Cancer

Adrenergic receptors and breast cancer:
The adrenergic compounds epinephrine and norepinephrine are important hormones/neurotransmitters released during stress. Their responses are mediated by the activation of adrenergic receptors. Our group has described the expression of α2-adrenergic receptors in tumor and non-tumor breast cell lines of human and murine origin. Its stimulation is associated with a significant increase in cell proliferation and tumor growth in different experimental models of breast cancer. We have also found that an α2 antagonist and a β2-adrenergic agonist (the latter usually used for the treatment of asthma) inhibit these parameters.
We described that β-adrenergic agonists have a significant effect on normal mouse mammary gland development and induce differentiation in experimental models of breast cancer. We study these compounds in vitro and in vivo regarding their biological effect and the intracellular signaling mechanisms involved in these responses. By understanding these mechanisms, it could be possible to determine which compounds (agonists and antagonists) may be useful as adjuvant treatments for breast cancer. These are promising findings with potential for clinical use as many of these compounds are widely used clinically for other specifications with minimal side effects. They could eventually complement existing therapies, especially in those cases in which resistance to them develops. Another possibility that we are analyzing is the reduction of the doses of drugs that have significant side effects (such as chemotherapy) through their joint administration with adrenergic agents of very low toxicity.
On the other hand, we have found by in silico studies that some of these receptors are related to better disease-free survival in some subtypes of breast tumors in patients, while other receptor subtypes have the opposite effect. We are currently completing these findings by testing the biological behavior of each adrenergic receptor subtype (by means of stable transfections) in experimental models of breast cancer in cultured cells. On the other hand, we study the conformation of these receptors in order to understand their structure and interaction with their ligands to allow the synthesis of new specific ligands. This line is carried out by Drs. Carlos David Bruque and Isabel Lüthy.

Role of FGFR2 and RUNX2 in the development of endocrine resistance in human breast cancer models:
About 70% of newly diagnosed breast cancers are estrogen receptor (ER)-positive, and thus, they are treated with endocrine therapies. However, with time patients may develop endocrine resistance. One of the mechanisms that drives hormone resistance in breast cancer is the cross talk of hormone receptors with growth factor signaling pathways. FGF/FGFR alterations are frequent in breast cancer patients and for this reason, FGFR inhibitors are being evaluated to overcome endocrine resistance. Patients with genetic alterations in the FGFR pathway have been selected in clinical trials for combined therapies with endocrine therapy plus FGFR inhibitors. However, the efficacy of the combination treatment was not as good as expected, suggesting the need to better understand which patients will benefit from this combination. We have previously shown that a) FGF2 increases breast cancer cell proliferation activating FGFR2 and ligand-independent hormone receptor signaling; b) A higher expression of RUNX2 was observed in hormone-independent (HI) murine tumor variants compared to the hormone-dependent (HD) counterparts and c) A positive loop between FGF2 and RUNX2 has been shown in bone tissue. The aim of our work is to evaluate the interplay between FGFR2 and RUNX2 in tumor progression and in response to endocrine or FGFR-targeted therapies using luminal human breast cancer models.
This line of work is carried out by Dr. Cecilia Pérez Piñero and Lic. María Sol Rodríguez in close collaboration with Drs. Claudia Lanari and Caroline Lamb, from the Hormonal Carcinogenesis Laboratory.