RESUMEN
Progesterone receptors (PRs) ligands are being tested in luminal breast cancer. There are mainly two PR isoforms, PRA and PRB, and their ratio (PRA/PRB) may be predictive of antiprogestin response. Our aim was to investigate: the impact of the PR isoform ratio on metastatic behaviour, the PR isoform ratio in paired primary tumours and lymph node metastases (LNM) and, the effect of antiprogestin/progestins on metastatic growth. Using murine and human metastatic models, we demonstrated that tumours with PRB > PRA (PRB-H) have a higher proliferation index but less metastatic ability than those with PRA > PRB (PRA-H). Antiprogestins and progestins inhibited metastatic burden in PRA-H and PRB-H models, respectively. In breast cancer samples, LNM retained the same PRA/PRB ratio as their matched primary tumours. Moreover, PRA-H LNM expressed higher total PR levels than the primary tumours. The expression of NDRG1, a metastasis suppressor protein, was higher in PRB-H compared to PRA-H tumours and was inversely regulated by antiprogestins/progestins. The binding of the corepressor SMRT at the progesterone responsive elements of the NDRG1 regulatory sequences, together with PRA, impeded its expression in PRA-H cells. Antiprogestins modulate the interplay between SMRT and AIB1 recruitment in PRA-H or PRB-H contexts regulating NDRG1 expression and thus, metastasis. In conclusion, we provide a mechanistic interpretation to explain the differential role of PR isoforms in metastatic growth and highlight the therapeutic benefit of using antiprogestins in PRA-H tumours. The therapeutic effect of progestins in PRB-H tumours is suggested.
Asunto(s)
Neoplasias de la Mama , Proteínas de Ciclo Celular , Péptidos y Proteínas de Señalización Intracelular , Receptores de Progesterona , Animales , Neoplasias de la Mama/patología , Proteínas de Ciclo Celular/metabolismo , Femenino , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones , Metástasis de la Neoplasia , Progesterona/farmacología , Progestinas/metabolismo , Isoformas de Proteínas/metabolismo , Receptores de Progesterona/metabolismoRESUMEN
Endocrine resistance may develop as a consequence of enhanced growth factor signaling. Fibroblast growth factor 2 (FGF2) consists of a low and several high molecular weight forms (HMW-FGF2). We previously demonstrated that antiprogestin-resistant mammary carcinomas display lower levels of progesterone receptor A isoforms (PRA) than B isoforms (PRB). Our aim was to evaluate the role of FGF2 isoforms in breast cancer progression. We evaluated FGF2 expression, cell proliferation, and pathway activation in models with different PRA/PRB ratios. We performed lentiviral infections of different FGF2 isoforms using the human hormone-responsive T47D-YA cells, engineered to only express PRA, and evaluated tumor growth, metastatic dissemination, and endocrine responsiveness. We assessed FGF2 expression and localization in 81 human breast cancer samples. Antiprogestin-resistant experimental mammary carcinomas with low PRA/PRB ratios and T47D-YB cells, which only express PRB, displayed higher levels of HMW-FGF2 than responsive variants. HMW-FGF2 overexpression in T47D-YA cells induced increased tumor growth, lung metastasis, and antiprogestin resistance compared to control tumors. In human breast carcinomas categorized by their PRA/PRB ratio, we found nuclear FGF2 expression in 55.6% of tumor cells. No differences were found between nuclear FGF2 expression and Ki67 proliferation index, tumor stage, or tumor grade. In low-grade tumor samples, moderate to high nuclear FGF2 levels were associated to carcinomas with low PRA/PRB ratio. In conclusion, we show that HMW-FGF2 isoforms are PRB targets which confer endocrine resistance and are localized in the nuclei of breast cancer samples. Hence, targeting intracellular FGF2 may contribute to overcome tumor progression.
Asunto(s)
Neoplasias de la Mama/genética , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Animales , Neoplasias de la Mama/patología , Línea Celular Tumoral , Femenino , Humanos , Ratones , Peso MolecularRESUMEN
El objetivo fue valorar la influencia de la quimioterapia neoadyuvante (QNA) en la modificación de la expresión de receptores de estrógeno (RE) y progesterona (RP). Mediante una revisión retrospectiva de historias clínicas fueron identificadas 52 mujeres con cáncer de mama tratadas con quimioterapia neoadyuvante en el hospital Eva Perón de San Martín, entre diciembre de 2005 y junio de 2015. Se estudió la expresión de receptores hormonales (RH) en el material de biopsia y sobre la pieza quirúrgica después del tratamiento neoadyuvante. Se realizó una valoración semicuantitativa de la intensidad de tinción para los receptores hormonales, considerándose negativas aquellas muestras con menos del 10% de las células teñidas. De las 51 pacientes, 30 de ellos presentaron respuesta parcial (RPa), 17 enfermedad estable (EE) y 4 progresión de enfermedad (PE). Si comparamos las muestras pre y post tratamiento, 32 (62.7%) no presentaron cambios en el grado histológico según el score de Nottingham, 9 (17.6%) disminuyeron su grado y 10 (19.6%) lo aumentaron. Respecto al estatus de RH hormonal, se mantuvo sin cambios en 34, 2 positivizaron los RH y 4 los negativizaron. Al valorar cada receptor de forma independiente, se aprecia positivización en 4 casos para RE y en 5 para RP. La negativización se produce en 4 casos para RE y 9 casos para RP. Se mantienen sin cambios 42 casos para RE y 37 RP. La exposición a la quimioterapia neoadyuvante se acompañó de cambios en la expresión de RH en un número reducido de casos, predominando dichos cambios en los RP (AU)
The aim was to assess the influence of neoadjuvant chemotherapy on the modification of estrogen receptors (ER) and progesterone receptors (PR). A retrospective review of clinical records identified 52 women with breast cancer treated with neoadjuvant chemotherapy at the Hospital Eva Perón de San Martin between December 2005 and June 2015. The expression of hormone receptors (HR) in the biopsy material and on the surgical specimen after neoadjuvant treatment, was studied. A semi-quantitative assessment of the intensity of staining for the hormonal receptors was performed, with negative samples being those with less than 10% of the stained cells. Of the 51 patients, 30 of them presented partial response, 17 stable disease and 4 disease progression. Comparing the pre and post treatment samples, 32 (62.7%) did not present changes in histological grade according to the Nottingham score, 9 (17.6%) decreased their grade and 10 (19.6%) increased it. Regarding HR status, it remained unchanged in 34, 2 positivized the HR and 4 negativized them. In an independent evaluation of each receptor, positivization is seen in 4 cases for RE and 5 for PR. Negativization occurs in 4 cases for RE and 9 cases for PR. Forty two cases remain unchanged for RE and 37 PR. The exposure to neoadjuvant chemotherapy was accompanied by changes in the expression of hormone receptors in a small number of cases, predominating these changes in PR (AU)