Anti-Angiogenic Treatments Interact with Steroid Secretion in Inflammatory Breast Cancer Triple Negative Cell Lines

SIMPLE SUMMARY: Inflammatory breast cancer (IBC) is the most aggressive breast cancer and is associated with poor prognosis. Exacerbated angiogenesis, lymphangiogenesis and lymphangiotropism are hallmarks of this tumour. Current antiangiogenic therapies have minimal effects on overall survival in IBC patients. Furthermore, it is well established that steroid hormones are strongly related to tumour development and progression, angiogenesis regulation and metastasis. We investigated the effect of different antiangiogenic therapies on steroid and angiogenic growth factor production using two inflammatory breast cancer cell lines. We reported that sex steroid hormones could regulate the production of angiogenic factors, since after the results, P4 and E2 were involved in VEGF production and androgens in the formation of vascular-like structures. Moreover, we reported that elevated intratumoural concentrations of T and E1SO4 could be associated with decreased metastatic rates and the promotion of tumour progression, respectively, and thus the measurement of sex steroids and growth factors may be useful to develop preventive and individualised therapeutic strategies. ABSTRACT: Human inflammatory breast cancer (IBC) is a highly angiogenic disease for which antiangiogenic therapy has demonstrated only a modest response, and the reason for this remains unknown. Thus, the purpose of this study was to determine the influence of different antiangiogenic therapies on in vitro and in vivo steroid hormone and angiogenic growth factor production using canine and human inflammatory breast carcinoma cell lines as well as the possible involvement of sex steroid hormones in angiogenesis. IPC-366 and SUM149 cell lines and xenotransplanted mice were treated with different concentrations of VEGF, SU5416, bevacizumab and celecoxib. Steroid hormone (progesterone, dehydroepiandrostenedione, androstenedione, testosterone, dihydrotestosterone, estrone sulphate and 17β-oestradiol), angiogenic growth factors (VEGF-A, VEGF-C and VEGF-D) and IL-8 determinations in culture media, tumour homogenate and serum samples were assayed by EIA. In vitro, progesterone- and 17β-oestradiol-induced VEGF production promoting cell proliferation and androgens are involved in the formation of vascular-like structures. In vivo, intratumoural testosterone concentrations were augmented and possibly associated with decreased metastatic rates, whereas elevated E1SO4 concentrations could promote tumour progression after antiangiogenic therapies. In conclusion, sex steroid hormones could regulate the production of angiogenic factors. The intratumoural measurement of sex steroids and growth factors may be useful to develop preventive and individualized therapeutic strategies.