TNF alpha acting on TNFR1 promotes breast cancer growth via p42/P44 MAPK, JNK, Akt and NF-kappa B-dependent pathways.

Tumor necrosis factor alpha (TNF alpha) enhances proliferation of chemically-induced mammary tumors and of T47D human cell line through not fully understood pathways. Here, we explored the intracellular signaling pathways triggered by TNF alpha, the participation of TNF alpha receptor (TNFR) 1 and TNFR2 and the molecular mechanism leading to breast cancer growth. We demonstrate that TNFalpha induced proliferation of C4HD murine mammary tumor cells and of T47D cells through the activation of p42/p44 MAPK, JNK, PI3-K/Akt pathways and nuclear factor-kappa B (NF-kappa B) transcriptional activation. A TNF alpha-specific mutein selectively binding to TNFR1 induced p42/p44 MAPK, JNK, Akt activation, NF-kappa B transcriptional activation and cell proliferation, just like wild-type TNF alpha, while a mutein selective for TNFR2 induced only p42/p44 MAPK activation. Interestingly, blockage of TNFR1 or TNFR2 with specific antibodies was enough to impair TNF alpha signaling and biological effect. Moreover, in vivo TNF alpha administration supported C4HD tumor growth. We also demonstrated, for the first time, that injection of a selective inhibitor of NF-kappa B activity, Bay 11-7082, resulted in regression of TNF alpha-promoted tumor. Bay 11-7082 blocked TNF alpha capacity to induce cell proliferation and up-regulation of cyclin D1 and of Bcl-xLin vivo and in vitro. Our results reveal evidence for TNF alpha as a breast tumor promoter, and provide novel data for a future therapeutic approach using TNF alpha antagonists and NF-kappa B pharmacological inhibitors in established breast cancer treatment.

Aromatase inhibitors and male breast cancer.

The majority of breast cancers in male patients are hormone receptor positive. Tamoxifen has proven to be successful in both adjuvant and metastatic settings and remains the standard of care. Given the improved outcomes in female patients with aromatase inhibitors (AI), these drugs have become a potential therapeutic tool for male patients. Preliminary data show effective suppression of oestradiol levels in males treated with AI and some reports have demonstrated objective responses. Here we report a case of a male patient with metastatic breast cancer treated with letrozole who achieved clinical response associated with a decrease in blood oestradiol levels.

Nuevas líneas celulares de cáncer de mama con receptores hormonales: su utilidad en la evaluación de compuestos terapéuticos / New cell lines of breast cancer with hormonal receptors: its utility in the therapeutic compounds evaluation

La mayoría de los cánceres de mama humanos son carcinomas ductales que expresan receptores hormonales, transitan por distintos estadios de hormono-dependencia y dan metástasis a distancia. No existen modelos experimentales cuyos tumores reúnan todas estas características. El modelo de inducción de carcinomas mamarios inducidos por acetato de medroxiprogesterona en el ratón, desarrollado hace años en nuestro laboratorio, es muy adecuado ya que la mayoría de los tumores inducidos son ductales, desarrollan metástasis en ganglios axilares y en pulmón, expresan altos niveles de receptores de estrógenos y progesterona cumple un rol proliferativo, mientras que en los tumores humanos, si bien cada vez hay más evidencias que sugieren que esta hormona cumple un rol importante, se les ha adjudicado a los estrógenos el rol protagónico. El objetivo de nuestras líneas de trabajo en general está orientada a jerarquizar el rol de los progestágenos en cáncer de mama. Para que un modelo experimental resulte interesante, debe reproducir en forma fidedigna la enfermedad humana y tener características intrínsecas tales como reproducibilidad, bajo costo, posibilidad de estudios in vitro, y uso de animales estándar. Nuestro modelo permite la posibilidad de diseñar estudios de carcinogénesis hormonal para evaluar cofactores que afecten el desarrollo de los tumores... (TRUNCADO)(AU)

Nuevas líneas celulares de cáncer de mama con receptores hormonales: su utilidad en la evaluación de compuestos terapéuticos / New cell lines of breast cancer with hormonal receptors: its utility in the therapeutic compounds evaluation

La mayoría de los cánceres de mama humanos son carcinomas ductales que expresan receptores hormonales, transitan por distintos estadios de hormono-dependencia y dan metástasis a distancia. No existen modelos experimentales cuyos tumores reúnan todas estas características. El modelo de inducción de carcinomas mamarios inducidos por acetato de medroxiprogesterona en el ratón, desarrollado hace años en nuestro laboratorio, es muy adecuado ya que la mayoría de los tumores inducidos son ductales, desarrollan metástasis en ganglios axilares y en pulmón, expresan altos niveles de receptores de estrógenos y progesterona cumple un rol proliferativo, mientras que en los tumores humanos, si bien cada vez hay más evidencias que sugieren que esta hormona cumple un rol importante, se les ha adjudicado a los estrógenos el rol protagónico. El objetivo de nuestras líneas de trabajo en general está orientada a jerarquizar el rol de los progestágenos en cáncer de mama. Para que un modelo experimental resulte interesante, debe reproducir en forma fidedigna la enfermedad humana y tener características intrínsecas tales como reproducibilidad, bajo costo, posibilidad de estudios in vitro, y uso de animales estándar. Nuestro modelo permite la posibilidad de diseñar estudios de carcinogénesis hormonal para evaluar cofactores que afecten el desarrollo de los tumores... (TRUNCADO)

Relationship between immune state and tumor growth rate in rats bearing progressive and non-progressive mammary tumors.

Impaired immune responses occur frequently in cancer patients or in tumor-bearing animals, but the mechanisms of the tumor-induced immune defects remain poorly understood. The aim of the present study was to determine the relevance of the immune system in the control of tumor growth. We have developed a model of progressive and non-progressive mammary tumor, chemically induced in female Wistar rats. In this model we evaluated the development of an immune response after immunization of rats bearing progressive and non-progressive tumors with a non-related antigen, such as sheep red blood cells. We also studied the activation state of peritoneal macrophages from animals bearing tumors by evaluating the production of free radicals. Our findings indicated that the cell-mediated immunity in rats bearing progressive tumors fails to respond to heterologous antigen in vivo, as demonstrated by a negative delayed-type hypersensitivity reaction, and is accompanied by minor nitric oxide production by peritoneal exudate cells as well as a lower capacity for macrophage activation. The study of non-progressive tumor-bearing rats indicated that the cell-mediated immune response was intact and an activated state of macrophages was found in vivo. The results described in this paper should be taken into account when therapies based on cancer vaccines are chosen for the treatment of cancer.

Receptors characterization of intraperitoneally N-nitroso-N-methylurea-induced mammary tumors in rats.

Mammary adenocarcinomas induces in female Sprague-Dawley rats by three intraperitoneal injections of N-nitroso-N-methylurea were studied in order to characterize their estrogen (ER), progesterone (PgR), prolactin (PRLR) and epidermal growth factor (EGFR) receptors. All samples evaluated showed the presence of ER and PgR in the cytosol fraction and PRLR amd EGFR in the membrane fraction. Q (fmol/mg) and K(d) (nM) values were as follows: ER, 56 +/- 11 and 0.5 +/- 0.1; PgR, 109 +/- 25 and 2.2 +/- 0.5 and PRLR, 335 +/- 75 and 0.5 +/- 0.2, respectively. In all tumors studied, two specific sites were found for EGFR, one with Q(1) = 22 +/- 9 and K(d1) = 0.6 +/- 0.3, and the other with Q(2) = 125 +/- 33 and K(d2) = 2.1 +/- 0.5. Receptor content was found to be independent of tumor histopathological variety. Displacement index (DI) with estradiol and tamoxifen of [I(3)H]E2-ER binding showed great heterogeneity, with values ranging from 0.01 to1.54. No correlation between ER content and DI values was found. Antiestrogenic binding sites were not found in the microsomal fraction of ten mammary tumors examined. Proliferation of this experimental mammary tumor may be regulated by a complex interaction of steroid and polypeptide hormones, as well as growth factors.

[Multiple neoplasms after a well succeeded treatment of Hodgkin's disease]. / Neoplasias múltiplas após tratamento bem sucedido de doença de Hodgkin.

The authors refer to a 21-year-old Caucasian (white) woman, who in 1977 presented fever and cervical and axillary adenopathy, whose biopsy showed nodular sclerosis Hodgkin's Disease, stage IIIB. The patient received six chemotherapy cycles associated with immunotherapy and supplemented with radiation therapy with good response. RESULTS--In 1985, after routine gynaecological examination and a hysterectomy, cervical intraepithelial neoplasia grade 3 (CIN 3) and atypic leiomyoma of the uterine body were diagnosed. Five years later, biopsies diagnosed invasive duct carcinoma in the right breast and homolateral axillary and cervical nodes. The patient was submitted to chemo and radiation therapy and died nine months later. CONCLUSION--The possibility of later occurrence of a second or multiple new malignancies in patients successfully treated for Hodgkin's Disease points out the need for a more complete long-term follow-up, including periodic mammography.

Progesterone induction of mammary carcinomas in BALB/c female mice. Correlation between progestin dependence and morphology.

We have demonstrated that medroxyprogesterone acetate (MPA), when administered in high doses, induces mammary carcinomas in virgin female BALB/c mice. Since one of the possible explanations for this effect was its progestagenic effects, we decided to investigate whether progesterone (Pg) alone could also induce mammary adenocarcinomas in our model and if MPA at doses lower than those used to establish the model was also carcinogenic. A total of 136 mice were subdivided into 3 groups: Group 1, 44 mice were implanted s.c. with 40 mg Pg silastic pellets at the beginning of the experiment, and 6 months later with a 20 mg Pg pellet; Group 2, 45 mice were similarly treated with MPA pellets; Group 3, 47 mice were inoculated s.c. with 40 mg MPA every three months. At the end of 20 months, 9 animals had developed mammary tumors in Group 1, 18 in Group 2 and 34 in Group 3 (actuarial incidence = 28%, 58%, and 98%, respectively); tumor latency was similar in all groups: 46.2 +/- 13.1, 51.3 +/- 9.9, and 50.1 +/- 2.1 weeks, respectively. Seven (Group 1), 14 (Group 2), and 25 (Group 3) tumors were transplanted into syngeneic mice to determine progestin dependence. All tumors, except one from Group 1, were histologically characterized. In Group 1 (Pg 60 mg), 4 tumors (67%) were infiltrating lobular carcinomas and 2 were ductal carcinomas (33%). In Group 2 (MPA 60 mg), 2 tumors (14%) were lobular and 12 were ductal adenocarcinomas (86%) (Group 1 vs Group 2: p < 0.05), whereas in Group 3 (MPA 160 mg), 8 were lobular carcinomas (32%) and 17 were ductal carcinomas (68%). In syngeneic passages all lobular tumors behaved as progestin independent (PI) and ductal tumors as progestin dependent (PD). All ductal tumors, except one, expressed estrogen receptors (ER) and progesterone receptors (PR), whereas receptor expression was variable in lobular carcinomas. It can be concluded that Pg induces mostly lobular, PI mammary tumors in BALB/c female mice. The fact that most MPA-induced tumors are ductal and PD suggests that the two hormones use different carcinogenic pathways.