ABSTRACT
Inhibitors of the mechanistic target of rapamycin (mTOR) are currently used to treat advanced metastatic breast cancer. However, whether an aggressive phenotype is sustained through adaptation or resistance to mTOR inhibition remains unknown. Here, complementary studies in human tumors, cancer models and cell lines reveal transcriptional reprogramming that supports metastasis in response to mTOR inhibition. This cancer feature is driven by EVI1 and SOX9. EVI1 functionally cooperates with and positively regulates SOX9, and promotes the transcriptional upregulation of key mTOR pathway components (REHB and RAPTOR) and of lung metastasis mediators (FSCN1 and SPARC). The expression of EVI1 and SOX9 is associated with stem cell-like and metastasis signatures, and their depletion impairs the metastatic potential of breast cancer cells. These results establish the mechanistic link between resistance to mTOR inhibition and cancer metastatic potential, thus enhancing our understanding of mTOR targeting failure.
Subject(s)
Breast Neoplasms/genetics , DNA-Binding Proteins/genetics , Lung Neoplasms/genetics , Proto-Oncogenes/genetics , SOX9 Transcription Factor/genetics , TOR Serine-Threonine Kinases/genetics , Transcription Factors/genetics , Adaptor Proteins, Signal Transducing/genetics , Adult , Aged , Breast Neoplasms/pathology , Carrier Proteins/genetics , Cell Proliferation/genetics , Female , Gene Expression Regulation, Neoplastic , Humans , Lung Neoplasms/pathology , Lung Neoplasms/secondary , MCF-7 Cells , MDS1 and EVI1 Complex Locus Protein , Microfilament Proteins/genetics , Middle Aged , Neoplasm Metastasis , Osteonectin/genetics , Regulatory-Associated Protein of mTOR , Signal Transduction/genetics , TOR Serine-Threonine Kinases/antagonists & inhibitors , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: Early-stage low-grade endometrial carcinoma has an excellent prognosis. In few cases local relapse and/or distant metastases can occur. We report the muscle as an unusual site of metastasis. CASE: A 69-year-old woman underwent surgery for FIGO Stage IA, grade 1 endometrioid adenocarcinoma of the endometrium. After four years she had local relapse without response to chemoradiation, requiring pelvic exanteration. Three years later she was diagnosed with a deltoid muscle metastasis confirmed histologically and bone metastases. After failing hormone therapy, chemotherapy was administered. She died eight months after diagnosis of the bone and muscle metastases. CONCLUSION: Low-risk endometrial carcinoma can behave like a high-risk group. Furthermore, this report describes, to our knowledge, the first case of endometrial carcinoma muscle metastasis.
Subject(s)
Carcinoma, Endometrioid/secondary , Endometrial Neoplasms/pathology , Muscle Neoplasms/secondary , Aged , Arm , Carcinoma, Endometrioid/diagnosis , Female , Humans , Muscle Neoplasms/diagnosis , Muscle, Skeletal , Neoplasm Recurrence, LocalABSTRACT
Cervical cancer is one of the most common types of cancer in women worldwide, with the highest rates observed in underdeveloped countries. In the last decades, its incidence has decreased after the implementation of screening programs, mainly in developed countries. Infection with high-risk oncogenic HPV is associated with precancerous lesions and cervical cancer. Advances in the understanding of the role of HPV in the etiology of high-grade cervical lesions (CIN 2/3) and cervical cancer have led to the development, evaluation and recommendation of two prophylactic HPV vaccines. This review article provides a summary of the studies related with their development and efficacy (AU)
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