HIF-1 activation induces doxorubicin resistance in MCF7 3-D spheroids via P-glycoprotein expression: a potential model of the chemo-resistance of invasive micropapillary carcinoma of the breast

BACKGROUND: Invasive micropapillary carcinoma (IMPC) of the breast is a distinct and aggressive variant of luminal type B breast cancer that does not respond to neoadjuvant chemotherapy. It is characterized by small pseudopapillary clusters of cancer cells with inverted cell polarity. To investigate whether hypoxia-inducible factor-1 (HIF-1) activation may be related to the drug resistance described in this tumor, we used MCF7 cancer cells cultured as 3-D spheroids, which morphologically simulate IMPC cell clusters. METHODS: HIF-1 activation was measured by EMSA and ELISA in MCF7 3-D spheroids and MCF7 monolayers. Binding of HIF-1α to MDR-1 gene promoter and modulation of P-glycoprotein (Pgp) expression was evaluated by ChIP assay and FACS analysis, respectively. Intracellular doxorubicin retention was measured by spectrofluorimetric assay and drug cytotoxicity by annexin V-FITC measurement and caspase activity assay. RESULTS: In MCF7 3-D spheroids HIF-1 was activated and recruited to participate to the transcriptional activity of MDR-1 gene, coding for Pgp. In addition, Pgp expression on the surface of cells obtained from 3-D spheroids was increased. MCF7 3-D spheroids accumulate less doxorubicin and are less sensitive to its cytotoxic effects than MCF7 cells cultured as monolayer. Finally, HIF-1α inhibition either by incubating cells with 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (a widely used HIF-1α inhibitor) or by transfecting cells with specific siRNA for HIF-1α significantly decreased the expression of Pgp on the surface of cells and increased the intracellular doxorubicin accumulation in MCF7 3-D spheroids. CONCLUSIONS: MCF7 breast cancer cells cultured as 3-D spheroids are resistant to doxorubicin and this resistance is associated with an increased Pgp expression in the plasma membrane via activation of HIF-1. The same mechanism may be suggested for IMPC drug resistance

Chondromatous differentiation in clear cell carcinoma of the ovary: A rare finding challenging the differential diagnosis

Objective: Ovarian surface epithelial tumors rarely have heterologous elements including bone or cartilage that may appear histologically benign or malignant. There are a few case reports in the literature of ovarian tumors containing chondromatous areas. Case: We report a clear cell carcinoma of the bilateral ovary showing chondromatous differentiation in a 56-year-old woman. Histopathologic study of the specimen showed clear cell carcinoma with many small foci of chondromatous differentiation. Immunohistochemical studies demonstrated positivity for S-100 confirming the diagnosis. The patient was alive with disease on chemotherapy for 16 months. Conclusion: A rare case of benign appearing chondromatous differentiation in an ovarian clear cell carcinoma of the ovary is described, and the significance of this finding is discussed. © 2008 Springer-Verlag

Inhibin ? and ß expression in ovarian stromal tumors and their histological equivalences

PubMed ID: 15059165Inhibin is a heterodimeric protein hormone that appears to be a sensitive immunohistochemical marker of sex cord-stromal tumors. Although sex cord-stromal tumors can usually be distinguished from ovarian epithelial tumors or their metastases by morphology or by using antibodies against intermediate filaments, the diagnosis remains difficult in rare situations in such cases as sarcomatoid granulosa-theca cell tumors, ovarian small cell carcinomas, or soft-tissue sarcomas. The purposes of this study were to examine inhibin ? and ß immunoreactivity in a wide range of gonadal stromal neoplasms and to assess its value in the differential diagnosis of problematic tumors. A total of 108 paraffin-embedded ovarian and extraovarian tumors were examined immunohistochemically by using anti-? inhibin and anti-ß inhibin. Inhibin ? immunostaining was identified in 46(81%) of 57 gonadal stromal tumors, one (14%) of seven endometrial stromal tumors, and one (50%) of two primary ovarian carcinoid tumors. Inhibin ß immunostaining was detected in 55(96%) of 57 gonadal stromal tumors, two (29%) of seven endometrial stromal tumors, one (50%) of two dysgerminomas, and in all of two (100%) primary ovarian carcinoid tumors. Inhibin ? expression was not detected in any ovarian surface epithelial tumor cells. Some surface epithelial tumors showed stromal inhibin ? (15% of cases) and inhibin ß (48% of cases) positivity. Weak immunoreactivity for inhibin ß was found in most (83% of cases) ovarian surface epithelial tumors. Two ovarian Burkitt lymphomas were negative for inhibin ? and ß. Inhibin ? is a sensitive immunohistochemical marker of gonadal stromal tumors and is of value in the differential diagnosis of ovarian neoplasia. Inhibin ß is a nonspecific marker for ovarian neoplasms, showing expression on tumor and stromal cells of different epithelial or stromal tumors. © Acta Obstet Gynecol Scand

Lipoadenofibroma of the endometrium: A rare variant of benign mullerian mixed tumor

PubMed ID: 18236054Objective: Adenofibroma is a form of mixed mesodermal tumor in which epithelial and stromal components are benign, and usually arises in the endometrium of postmenopausal women. We report a case of lipoadenofibroma of the endometrium that appeared as an intracavitary mass, which is very unusual because endometrioid adenofibroma rarely contains mature adipose tissue, only the second such case described in detail. Case: An endometrial polypoid mass measuring 1,5 cm with maximum diameter was found incidentally during total abdominal hysterectomy for keratinizing large cell carcinoma of the cervix in a 60-year-old woman. The endometrial polypoid mass was found to be a lipoadenofibroma composed predominantly of collagenated fibrous stroma populated by cystically dilated and occasionally crowded glands lined with proliferative endometrium, intermingled with abundant mature adipose tissue. Conclusion: We suggest that uterine adenofibromas with lipomatous areas belong to the family of mixed tumor of Mullerian origin. We discuss the pathogenesis of this entity and review the previously documented similar cases. © 2008 Springer-Verlag