Objective: Inhibins and activins are members of the transforming growth factor b superfamily and are known to modulate the growth and differentiation of several cell types. The present study investigated the localization of inhibin and activin subunits in human normal and pathological breast tissues. Design: A cross-sectional study comparing the expression of inhibin/activin subunits a, bA and bB in surgical specimens from women undergoing reductive mammoplasty (classified, according to the phase of the menstrual cycle, as follicular, luteal, or postmenopausal), and patients submitted to lumpectomy for fibrocystic disease, benign (intraductal papilloma, adenomyoepithelioma, and hamartoma) or malignant breast neoplams (intraductal, intralobular, and invasive carcinoma). Methods: Immunohistochemistry was used to localize inhibin a and activin bA and bB subunits in the cytoplasm of epithelial cells of mammary glands. Dimeric activin A, inhibin A and inhibin B were measured by specific two-site enzyme immunoassay in the cystic fluid collected from patients with fibrocystic disease. Results: An intense staining for the a inhibin subunit and a mild staining for bA and bB subunits were present in samples obtained from normal breast tissue regardless of menstrual cycle phase, and in fibrocystic disease and benign neoplasms. Carcinoma cells stained weakly to moderately for a subunit and were negative for bA and bB subunits. Fibrocystic disease was associated with absence of bA subunit expression in normal epithelial cells and intense staining for all subunits in the apocrine cells. Immunoreactive inhibin A, inhibin B, and activin A were also present in cystic fluid, suggesting a local secretion of these proteins. Conclusion: These data suggest a local expression and secretion of inhibin and activin in human normal, fibrocystic disease and neoplastic breast tissues. The low expression of these proteins may facilitate abnormal cell proliferation in breast carcinoma.

Objective: Inhibin and activin are proteins produced by ovarian granulosa cells and testicular Sertoli cells and are members of the transforming growth factor-b superfamily. Since increased circulating levels of immunoreactive inhibin were detected in women with malignant ovarian tumors, they were proposed as tumor markers for ovarian carcinoma. Immunohistochemical studies later confirmed the presence of inhibin and activin subunits in granulosa cell tumors and epithelial ovarian cancer, as well as in Sertoli and Leydig cell testicular cancer. However, there is discrepant information on the detection of inhibin and activin in malignant germ cell tumors (MGCT). The aim of the present study was to evaluate the immunohistochemical expression of the inhibin/activin a, bA and bB subunits in ovarian and testicular MGCT specimens using polyclonal antisera. Methods: The ovarian tissue samples were composed of 19 MGCT, including dysgerminoma ðn ¼ 18Þ and yolk sac tumor ðn ¼ 1Þ. The testis specimens included classic seminomas ðn ¼ 20Þ; embryonal carcinomas ðn ¼ 7Þ; choriocarcinomas ðn ¼ 2Þ; and yolk sac tumor ðn ¼ 1Þ. Results: Ovarian and testicular malignant germ cell tumors expressed positive staining for inhibin/ activin a, bA and bB subunits, with some variations between and within individual tumors: while ovarian dysgerminomas were diffusely positive for a, bA and bB, testicular tumors expressed a and bB subunits, whereas bA staining was weak. Conclusions:The present results show positive staining for inhibin/activin subunits in ovarian and testicular MGCT, suggesting a possible role in tumorigenesis with the resultant clinical implication.

Homeobox genes are involved in neoplastic transformation of both epithelial and hemopoietic tissues. The divergent homeobox gene HEX is expressed in the anterior visceral endoderm during early mouse development and in some adult tissues of endodermal origin, including liver and thyroid. Whereas a role in leukemyogenesis has been proposed already, few data are available on the involvement of HEX in human epithelial tumors. Herein, we analyzed HEX expression and subcellular localization in a series of 55 human thyroid tumors and in several tumoral cell lines. HEX mRNA was detected by RT-PCR either in normal tissues or in thyroid adenomas and differentiated (papillary and follicular) carcinomas. HEX mRNA was also expressed in most undifferentiated carcinomas. Subcellular localization of HEX protein was investigated by immunohistochemistry. In normal tissues and adenomas, HEX protein was present both in nucleus and cytoplasm. In contrast, both differentiated and undifferentiated carcinomas, as well as the tumoral cell lines investigated, showed HEX protein only in the cytoplasm. These findings suggest that regulation of HEX entry in the nucleus of thyrocytes may represent a critical step during human thyroid tumorigenesis.

Objective: To evaluate the prognostic value of the balance between apoptosis and proliferation in non-small-cell lung cancer (NSCLC). Methods: Paraffin-embedded sections from a consecutive series of radically resected NSCLCs were scored for apoptosis (in situ DNA nick end labeling assay) and proliferation (immunohistochemistry for MIB-1). A total of 1,000 cells were counted per case, to obtain apoptotic (AI) and MIB-1 indices. Other potential prognostic indicators (pT, pN, pStage and histology) and p53 status were also evaluated. Results: Univariate analysis showed that adenocarcinomatous histotype (p = 0.03), nodal involvement (p = 0.04), higher pStage (p = 0.001) and the combination of low AI and high MIB-1 expression (p = 0.03) were associated with poorer outcome. The significant prognostic value of the combination ‘low AI/high MIB-1’ was also confirmed in a multivariate analysis after adjustment for other covariates. Conclusion: These results underline the importance of considering apoptosis and proliferation together to identify a subgroup of NSCLC associated with poor survival.

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