Survivin family proteins as novel molecular determinants of doxorubicin resistance in organotypic human breast tumors.

INTRODUCTION: The molecular determinants of breast cancer resistance to first-line anthracycline-containing chemotherapy are unknown. METHODS: We examined the response to doxorubicin of organotypic cultures of primary human breast tumors ex vivo with respect to cell proliferation, DNA damage and modulation of apoptosis. Samples were analyzed for genome-wide modulation of cell death pathways, differential activation of p53, and the role of survivin family molecules in drug resistance. Rational drug combination regimens were explored by high-throughput screening, and validated in model breast cancer cell types. RESULTS: Doxorubicin treatment segregated organotypic human breast tumors into distinct Responder or Non Responder groups, characterized by differential proliferative index, stabilization of p53, and induction of apoptosis. Conversely, tumor histotype, hormone receptor or human epidermal growth factor receptor-2 (HER2) status did not influence chemotherapy sensitivity. Global analysis of cell death pathways identified survivin and its alternatively spliced form, survivin-ΔEx3 as uniquely overexpressed in Non Responder breast tumors. Forced expression of survivin-ΔEx3 preserved cell viability and prevented doxorubicin-induced apoptosis in breast cancer cell types. High-throughput pharmacologic targeting of survivin family proteins with a small-molecule survivin suppressant currently in the clinic (YM155) selectively potentiated the effect of doxorubicin, but not other chemotherapeutics in breast cancer cell types, and induced tumor cell apoptosis. CONCLUSIONS: Survivin family proteins are novel effectors of doxorubicin resistance in chemotherapy-naive breast cancer. The incorporation of survivin antagonist(s) in anthracycline-containing regimens may have improved clinical activity in these patients.

The Ribonucleic Complex HuR-MALAT1 Represses CD133 Expression and Suppresses Epithelial-Mesenchymal Transition in Breast Cancer.

Epithelial-to-mesenchymal transition (EMT) is a core process underlying cell movement during embryonic development and morphogenesis. Cancer cells hijack this developmental program to execute a multi-step cascade, leading to tumorigenesis and metastasis. CD133 (PROM1), a marker of cancer stem cells, has been shown to facilitate EMT in various cancers, but the regulatory networks controlling CD133 gene expression and function in cancer remain incompletely delineated. In this study, we show that a ribonucleoprotein complex including the long noncoding RNA MALAT1 and the RNA-binding protein HuR (ELAVL1) binds the CD133 promoter region to regulate its expression. In luminal nonmetastatic MCF-7 breast cancer cells, HuR silencing was sufficient to upregulate N-cadherin (CDH2) and CD133 along with a migratory and mesenchymal-like phenotype. Furthermore, we found that in the basal-like metastatic cell line MDA-MB-231 and primary triple-negative breast cancer tumor cells, the repressor complex was absent from the CD133-regulatory region, but was present in the MCF-7 and primary ER+ tumor cells. The absence of the complex from basal-like cells was attributed to diminished expression of MALAT1, which, when overexpressed, dampened CD133 levels. In conclusion, our findings suggest that the failure of a repressive complex to form or stabilize in breast cancer promotes CD133 upregulation and an EMT-like program, providing new mechanistic insights underlying the control of prometastatic processes. Cancer Res; 76(9); 2626-36. ©2016 AACR.

Multidisciplinary approach to follicular thyroid carcinoma with giant mandibular and multiple sites metastases Case report.

UNLABELLED: Multidisciplinary approach to follicular thyroid carcinoma with giant mandibular and multiple sites metastases. Case report Metastatic tumors generally have poor prognosis, with short survival period and rarely indication to surgical treatment. In case of thyroid-differentiated cancer with distant metastases, prognosis is usually better, because of the possibility of treating metastasis by Radio Ablation by 131Iodine, after surgery. We report the case of a 65 years old woman, presenting with a giant mandibular metastasis from follicular thyroid carcinoma, originating from a cervico-mediastinal nonfunctioning goiter, with lung metastases. After the diagnostic work-up, she underwent left hemi-mandibulectomy, reconstruction by the placement of a precustomized titanium plate with condylar prosthesis and total thyroidectomy. Subsequently the Patient was treated by Radio Ablation by 131 Iodine, in four consecutive sessions. She is alive with no progression of the neoplasm after forty-six months follow-up. Even in advanced differentiated thyroid carcinoma, surgery should be taken into consideration, to treat the patient by complementary therapies and to improve the prognosis in term of survival. KEY WORDS: Advanced differentiated thyroid carcinoma, Metastatic differentiated thyroid carcinoma.

Thyroid microcarcinoma approach: a ten year experience.

AIM: To optimize thyroid microcarcinoma approach, through a retrospective examination of Authors' experience and literature review. MATERIALS: Characteristics, treatment and outcomes of patients affected with thyroid microcarcinoma were examined: among 1733 patients operated on for thyroid diseases at Endocrine Surgery Unit of San Paolo Hospital in Milan, from 2001 to 2011, 104 (6.0%) resulted affected with microcarcinoma. Twenty (19.2%) had pre-operative and 84 (80.8%) post-operative diagnosis, 11 with (N+) and 93 without (N0) lymph node metastasis. Eighty-five patients underwent total thyroidectomy, 11 (N+) total thyroidectomy with lymphoadenectomy and 8 lobectomy, 2 radicalized in thyroidectomy. All patients underwent Levo-thyroxine suppressive therapy, 25 (24.0%) 131I ablation. Differences between N0 and N+ patients were researched. RESULTS: Neither recurrences nor death at a mean follow-up of 5.6 years. Tumour was multifocal and in thyroid with no other diseases in N+, in a greater rate than in N0 patients. DISCUSSION: Microcarcinoma generally has an indolent course, but sometimes it presents with nodal metastasis. For this reason its treatment in literature is still largely debated. CONCLUSION: In cases of pre-operative diagnosis of microcarcinoma without lymph node metastasis, we propose total thyroidectomy; otherwise, total thyroidectomy with lymphoadenectomy. In cases of post-operative diagnosis, after a partial resection, only selected cases on the basis of patients' and tumour features require a completion total thyroidectomy. We propose Levo-thyroxine suppressive therapy to all patients, 131I ablation in cases of lymphatic metastasis and only in selected cases without metastasis, on the basis of patients' and tumour aspects (age, sex, histological variant, multifocality).