ABSTRACT
Understanding the mechanisms of breast cancer cell communication underlying cell spreading and metastasis formation is fundamental for developing new therapies. ID4 is a proto-oncogene overexpressed in the basal-like subtype of triple-negative breast cancer (TNBC), where it promotes angiogenesis, cancer stem cells, and BRACA1 misfunction. Here, we show that ID4 expression in BC cells correlates with the activation of motility pathways and promotes the production of VEGFA, which stimulates the interaction of VEGFR2 and integrin ß3 in a paracrine fashion. This interaction induces the downstream focal adhesion pathway favoring migration, invasion, and stress fiber formation. Furthermore, ID4/ VEGFA/ VEGFR2/ integrin ß3 signaling stimulates the nuclear translocation and activation of the Hippo pathway member's YAP and TAZ, two critical executors for cancer initiation and progression. Our study provides new insights into the oncogenic roles of ID4 in tumor cell migration and YAP/TAZ pathway activation, suggesting VEGFA/ VEGFR2/ integrin ß3 axis as a potential target for BC treatment.
Subject(s)
Breast Neoplasms , Integrin beta3 , Humans , Female , Integrin beta3/metabolism , Cell Line, Tumor , Signal Transduction , Hippo Signaling Pathway , Vascular Endothelial Growth Factor A , Inhibitor of Differentiation ProteinsABSTRACT
Vascular Endothelial Growth Factor A (VEGFA) is the most commonly expressed angiogenic growth factor in solid tumors and is generated as multiple isoforms through alternative mRNA splicing. Here, we show that lncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) and ID4 (inhibitor of DNA-binding 4) protein, previously referred to as regulators of linear isoforms of VEGFA, induce back-splicing of VEGFA exon 7, producing circular RNA circ_0076611. Circ_0076611 is detectable in triple-negative breast cancer (TNBC) cells and tissues, in exosomes released from TNBC cells and in the serum of breast cancer patients. Circ_0076611 interacts with a variety of proliferation-related transcripts, included MYC and VEGFA mRNAs, and increases cell proliferation and migration of TNBC cells. Mechanistically, circ_0076611 favors the expression of its target mRNAs by facilitating their interaction with components of the translation initiation machinery. These results add further complexity to the multiple VEGFA isoforms expressed in cancer cells and highlight the relevance of post-transcriptional regulation of VEGFA expression in TNBC cells.
Subject(s)
MicroRNAs , RNA, Long Noncoding , Triple Negative Breast Neoplasms , Humans , MicroRNAs/genetics , Protein Isoforms/genetics , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Triple Negative Breast Neoplasms/metabolism , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/metabolismABSTRACT
In metastatic breast cancer (mBC), the change of human epidermal growth factor receptor 2 (HER2) status between primary and metastatic lesions is widely recognized, however clinical implications are unknown. Our study address the question if relevant differences exist between subjects who preserve the HER2 status and those who gain the HER2 positivity when relapsed. Data of patients affected by HER2-positive mBC, treated with pertuzumab and/or trastuzumab-emtansine (T-DM1) in a real-world setting at 45 Italian cancer centers were retrospectively collected and analyzed. From 2003 to 2017, 491 HER2-positive mBC patients were included. Of these, 102 (20.7%) had been initially diagnosed as HER2-negative early BC. Estrogen and/or progesterone receptor were more expressed in patients with HER2-discordance compared to patients with HER2-concordant status (p < 0.0001 and p = 0.006, respectively). HER2-discordant tumors were characterized also by a lower rate of brain metastases (p = 0.01) and a longer disease free interval (p < 0.0001). Median overall survival was longer, although not statistically significant, in the subgroup of patients with HER2-discordant cancer with respect to patients with HER2-concordant status (140 vs 78 months, p = 0.07). Our findings suggest that patients with HER2-positive mBC with discordant HER2 status in early BC may have different clinical, biological and prognostic behavior compared to HER2-concordant patients.
Subject(s)
Brain Neoplasms/genetics , Breast Neoplasms/genetics , Prognosis , Receptor, ErbB-2/genetics , Ado-Trastuzumab Emtansine/administration & dosage , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Brain Neoplasms/drug therapy , Brain Neoplasms/epidemiology , Brain Neoplasms/pathology , Breast Neoplasms/drug therapy , Breast Neoplasms/epidemiology , Breast Neoplasms/pathology , Disease-Free Survival , Female , Humans , Middle Aged , Neoplasm Metastasis , Receptors, Progesterone/geneticsABSTRACT
Localization of metastases into the parotid gland is a very uncommon event. Usually they arise from primary tumors located in the head and neck, mainly melanoma or epidermoid carcinoma of the skin, while other histotypes, from others anatomical districts, hardly have a metastatic spread to the parotid. Myxoid liposarcoma (MLS) is a rare malignant tumor of the soft tissue that mainly occurs in the extremities, representing the second most common subtype of liposarcoma. Although it is typical for liposarcomas to metastasize to the lungs, it is known that MLS can spread also to extra pulmonary sites. The authors report a case of myxoid liposarcoma of the left thigh in a 64-year-old man, with an unusual metastatic double presentation to the contralateral forearm first and to the parotid gland then. MLS with metastatic disease to the parotid gland is an extremely rare event with very few cases reported in the English literature.
