The Beta2-adrenergic agonist salbutamol synergizes with paclitaxel on cell proliferation and tumor growth in triple negative breast cancer models.

PURPOSE: Globally breast cancer accounts for 24.5% in incidence and 15.5% in cancer deaths in women. The triple-negative subtype lacks any specific therapy and is treated with chemotherapy, resulting in significant side-effects. We aimed to investigate if the dose of chemotherapeutic drugs could be diminished by co-administering it with the ß2-agonist salbutamol. METHODS: Cell proliferation was measured by thymidine incorporation; gene expression, by real-time PCR and protein phosphorylation by WB. Apoptosis was assessed by acridine orange / ethidium bromide and TUNEL tests. Public patient databases were consulted. Cells were inoculated to nude mice and their growth assessed. RESULTS: The ß2-agonist salbutamol synergizes in MDA-MB-231 cells in vitro with paclitaxel and doxorubicin on cell proliferation through ADRB2 receptors, while the ß-blocker propranolol does not. The expression of this receptor was assessed in patient databases and other cell lines. Triple negative samples had the lowest expression. Salbutamol and paclitaxel decreased MDA-MB-231 cell proliferation while their combination further inhibited it. The pathways involved were analyzed. When these cells were inoculated to nude mice, paclitaxel and salbutamol inhibited tumor growth. The combined effect was significantly greater. Paclitaxel increased the expression of MDR1 while salbutamol partially reversed this increase. CONCLUSION: While the effect of salbutamol was mainly on cell proliferation, suboptimal concentrations of paclitaxel provoked a very important enhancement of apoptosis. The latter enhanced transporter proteins as MDR1, whose expression were diminished by salbutamol. The expression of ADRB2 should be assessed in the biopsy or tumor to eventually select patients that could benefit from salbutamol repurposing.

Adrenergic receptors in breast cancer.

Breast cancer is the most diagnosed malignancy in women worldwide and in the majority of the countries. Breast cancers are classified on the expression of estrogen and progesterone receptor expression and overexpression of human epidermal growth factor receptor 2 (HER2) as luminal, HER2+ and triple negative breast cancer. The intrinsic molecular subtypes match this classification. Cancer diagnosis and treatment cause distress. In both acute and chronic stress, the secreted catecholamines adrenaline and noradrenaline trigger the "fight-or-flight" response. This chapter focuses on the actions of the ß2 and α2 adrenergic receptors in several models of breast cancer. The actions of these receptors depend on the model used to investigate them. The ß2-adrenergic receptors seem to exert a dual action. They can directly act on the epithelial cells inhibiting cell proliferation and migration/invasion and indirectly upon the immune microenvironment. The proportion of ß2 receptors in each compartment could, therefore, lean the scale to an inhibition or to an exacerbation of tumor growth, invasion and metastasis. All the work points to a beneficial or neutral action of ß-blockers on breast cancer. With respect to α2-adrenergic receptors, the investigation performed by our group suggest that the α2B and the α2C receptors are linked to enhanced cell proliferation and tumor growth acting through both the epithelial and the stromal (fibroblastic) compartments while α2A could be beneficial for patients. Some adrenergic compounds could be repurposed for breast cancer treatment due to their very low side effects and very well-known pharmacology.

New Insights in the Interaction of FGF/FGFR and Steroid Receptor Signaling in Breast Cancer.

Luminal breast cancer (BrCa) has a favorable prognosis compared with other tumor subtypes. However, with time, tumors may evolve and lead to disease progression; thus, there is a great interest in unraveling the mechanisms that drive tumor metastasis and endocrine resistance. In this review, we focus on one of the many pathways that have been involved in tumor progression, the fibroblast growth factor/fibroblast growth factor receptor (FGFR) axis. We emphasize in data obtained from in vivo experimental models that we believe that in luminal BrCa, tumor growth relies in a crosstalk with the stromal tissue. We revisited the studies that illustrate the interaction between hormone receptors and FGFR. We also highlight the most frequent alterations found in BrCa cell lines and provide a short review on the trials that use FGFR inhibitors in combination with endocrine therapies. Analysis of these data suggests there are many players involved in this pathway that might be also targeted to decrease FGF signaling, in addition to specific FGFR inhibitors that may be exploited to increase their efficacy.

FGF2 induces breast cancer growth through ligand-independent activation and recruitment of ERα and PRBΔ4 isoform to MYC regulatory sequences.

Progression to hormone-independent growth leading to endocrine therapy resistance occurs in a high proportion of patients with estrogen receptor alpha (ERα) and progesterone receptors (PR) positive breast cancer. We and others have previously shown that estrogen- and progestin-induced tumor growth requires ERα and PR interaction at their target genes. Here, we show that fibroblast growth factor 2 (FGF2)-induces cell proliferation and tumor growth through hormone-independent ERα and PR activation and their interaction at the MYC enhancer and proximal promoter. MYC inhibitors, antiestrogens or antiprogestins reverted FGF2-induced effects. LC-MS/MS identified 700 canonical proteins recruited to MYC regulatory sequences after FGF2 stimulation, 397 of which required active ERα (ERα-dependent). We identified ERα-dependent proteins regulating transcription that, after FGF2 treatment, were recruited to the enhancer as well as proteins involved in transcription initiation that were recruited to the proximal promoter. Also, among the ERα-dependent and independent proteins detected at both sites, PR isoforms A and B as well as the novel protein product PRBΔ4 were found. PRBΔ4 lacks the hormone-binding domain and was able to induce reporter gene expression from estrogen-regulated elements and to increase cell proliferation when cells were stimulated with FGF2 but not by progestins. Analysis of the Cancer Genome Atlas data set revealed that PRBΔ4 expression is associated with worse overall survival in luminal breast cancer patients. This discovery provides a new mechanism by which growth factor signaling can engage nonclassical hormone receptor isoforms such as PRBΔ4, which interacts with growth-factor activated ERα and PR to stimulate MYC gene expression and hence progression to endocrine resistance.

Aporte de los dosajes de inhibina B y hormona antimulleriana al conocimiento de la función ovárica en mujeres jóvenes con cáncer de mama posterior a la quimio y hormonoterapia / Dosages contribution of inhibin B and AMH knowledge of ovarian function in young women with breast cancer back to chemo and hormone therapy

Los estudios de hormona antimulleriana (HAM) e inhibina B tienen una implicancia importante en la fertilidad y salud sexual (su ausencia impide el embarazo) y en la salud ósea. Las investigaciones al respecto se realizaron en especial en endocrinología y reproducción desde 2000. Recientemente, ha llamado nuestra atención su estudio en diferentes centros mundiales en pacientes premenopáusicas con cáncer de mama temprano, posterior a la quimio y hormonoterapia, ya que su evaluación es un marcador, junto con la amenorrea, de la inactividad del ovario.