RANK is an independent biomarker of poor prognosis in estrogen receptor-negative breast cancer and a therapeutic target in patient-derived xenografts

Despite strong preclinical data, the therapeutic benefit of the RANKL inhibitor denosumab in BC patients, beyond its bone-related effects, is unclear. Here, we investigated the prognostic value of RANK expression and its functionality in human BC. We analyzed RANK and RANKL expression in more than 1500 BC cases (777 being estrogen receptor-negative (ER-)) from four independent cohorts. We confirmed that RANK is more frequently expressed in ER- tumors, but it is also found in a subset of ER+ tumors. In ER- BC, RANK expression was independently associated with poor outcome, especially in postmenopausal patients and those who received adjuvant chemotherapy. Gene expression analyses unraveled distinct biology associated with RANK in relation to ER expression and menopause, and evidenced enhanced RANK activation in ER- postmenopausal tumors, together with regulation of metabolic pathways. Functional studies and transcriptomic analyses in ER- RANK+ patients-derived orthoxenografts demonstrated that activation of RANK signaling pathway promotes tumor cell proliferation and stemness, and regulates multiple biological processes including tumor immune surveillance and metabolism. Our results demonstrate that RANK expression is an independent poor prognosis biomarker in postmenopausal ER- BC patients and support the rational of using RANK pathway inhibitors in combination with chemotherapy in ER- BC.N

EMBOLISMO POR POLIMETIL METACRILATO POSTERIOR A INYECCIÓN SUBCUTÁNEA EN REGIÓN GLÚTEA. A PROPÓSITO DE UN CASO

El polimetil-metacrilato es un polímero de alta resistencia al impacto, ampliamente utilizado en diferentes camposde la medicina, sin embargo, aún no está clara su indicación como relleno glúteo. A pesar de su aparente inocuidad, se hanpresentado complicaciones durante su uso como granulomas y nódulos palpables. Se han reportado casos de embolismopulmonar por polimetil-metacrilato posterior a vertebroplastias. Sin embargo, no se encontró reporte bibliográfico de casosde embolismo pulmonar con su uso en procedimientos estéticos. Presentamos caso de paciente femenino de 31 años de edad,quien 4 horas luego de la inyección de 500 cm3 de polimetil-metacrilato en cada región glútea, presenta disnea en reposo deaparición súbita con tos seca y palpitaciones, disminución de agudeza visual y petequias generalizadas. Se diagnostica probableembolismo pulmonar por polimetil-metacrilato y retinopatía de Purtscher. Existe similitud clínica e imaginología del caso enestudio con embolismo por silicone, y las imágenes del fondo de ojo semejan la obstrucción de pequeñas arteriolas retinianascompatibles con este diagnóstico. Se sugieren nuevas investigaciones en el uso de polimetil-metacrilato como procedimientoestético en pro de la seguridad y en beneficio de los pacientes.ABSTRACT: Polymethyl-methacrylate is a high impact resistant polymer, widely used in different medicine fields, howeverits indication in buttock implants is still not clear. Even though its apparent innocuity, it has presented complications likegranulomas and palpable nodules. There have been reported cases of pulmonary embolism caused by polimetil-metacrilatosecondary to vertebroplasties. However, there have been no bibliographic cases of pulmonary embolism due to its use inaesthetic procedures. We present a case of a woman patient of 31 years old, who 4 hours after 500 cc injection of polymethyl-Methacrylate in each buttock, presents rest dyspnea with abrupt dry cough and palpitations, reduction in visual acuity andgeneralized petechiae. It is diagnosed probable pulmonary embolism by polimetil-metacrilato and Purtscher retinopathy. Thereis a clinical and imaginological similitude between this case and silicone embolism and the images of fondoscopy are similarto those of small retinian arteriole obstruction compatible with the diagnosis. Thereby, it is suggested new investigations inthe use of polymethyl-methacrylate as esthetic procedure in favor of the patient’s security and benefit

RANK is a poor prognosis marker and a therapeutic target in ER-negative postmenopausal breast cancer

Despite strong preclinical data, the therapeutic benefit of the RANKL inhibitor, denosumab, in breast cancer patients, beyond the bone, is unclear. Aiming to select patients who may benefit from denosumab, we hereby analyzed RANK and RANKL protein expression in more than 2000 breast tumors (777 estrogen receptor-negative, ER-) from four independent cohorts. RANK protein expression was more frequent in ER- tumors, where it associated with poor outcome and poor response to chemotherapy. In ER- breast cancer patient-derived orthoxenografts (PDXs), RANKL inhibition reduced tumor cell proliferation and stemness, regulated tumor immunity and metabolism, and improved response to chemotherapy.Intriguingly, tumor RANK protein expression associated with poor prognosis in postmenopausal breast cancer patients, activation of NFKB signaling and modulation of immune and metabolic pathways, suggesting that RANK signaling increases after menopause. Our results demonstrate that RANK expression is an independent biomarker of poor prognosis in postmenopausal ER- breast cancer patients and support the therapeutic benefit of RANK pathway inhibitors, such as denosumab, in breast cancer patients with RANK+ ER- tumors after menopause