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1. Combination Treatment of Retinoic Acid Plus Focal Adhesion Kinase Inhibitor Prevents Tumor Growth and Breast Cancer Cell Metastasis

Author

Ana Carla Castro-Guijarro, Fiorella Vanderhoeven, Joselina Magali Mondaca, Analía Lourdes Redondo, Felipe Carlos Martin Zoppino, Juan Manuel Fernandez-Muñoz, Angel Matias Sanchez, and Marina Inés Flamini

Subjects
retinoids, FAK inhibitor, cell motility, metastasis, breast cancer, Cytology, QH573-671
Abstract

All-trans retinoic acid (RA), the primary metabolite of vitamin A, controls the development and homeostasis of organisms and tissues. RA and its natural and synthetic derivatives, both known as retinoids, are promising agents in treating and chemopreventing different neoplasias, including breast cancer (BC). Focal adhesion kinase (FAK) is a crucial regulator of cell migration, and its overexpression is associated with tumor metastatic behavior. Thus, pharmaceutical FAK inhibitors (FAKi) have been developed to counter its action. In this work, we hypothesize that the RA plus FAKi (RA + FAKi) approach could improve the inhibition of tumor progression. By in silico analysis and its subsequent validation by qPCR, we confirmed RARA, SRC, and PTK2 (encoding RARα, Src, and FAK, respectively) overexpression in all breast cells tested. We also showed a different pattern of genes up/down-regulated between RA-resistant and RA-sensitive BC cells. In addition, we demonstrated that both RA-resistant BC cells (MDA-MB-231 and MDA-MB-468) display the same behavior after RA treatment, modulating the expression of genes involved in Src-FAK signaling. Furthermore, we demonstrated that although RA and FAKi administered separately decrease viability, adhesion, and migration in mammary adenocarcinoma LM3 cells, their combination exerts a higher effect. Additionally, we show that both drugs individually, as well as in combination, induce the expression of apoptosis markers such as active-caspase-3 and cleaved-PARP1. We also provided evidence that RA effects are extrapolated to other cancer cells, including T-47D BC and the human cervical carcinoma HeLa cells. In an orthotopic assay of LM3 tumor growth, whereas RA and FAKi administered separately reduced tumor growth, the combined treatment induced a more potent inhibition increasing mice survival. Moreover, in an experimental metastatic assay, RA significantly reduced metastatic lung dissemination of LM3 cells. Overall, these results indicate that RA resistance could reflect deregulation of most RA-target genes, including genes encoding components of the Src-FAK pathway. Our study demonstrates that RA plays an essential role in disrupting BC tumor growth and metastatic dissemination in vitro and in vivo by controlling FAK expression and localization. RA plus FAKi exacerbate these effects, thus suggesting that the sensitivity to RA therapies could be increased with FAKi coadministration in BC tumors.

Published
2022
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2. Molecular Basis of LH Action on Breast Cancer Cell Migration and Invasion via Kinase and Scaffold Proteins

Author

Joselina Magali Mondaca, Ivonne Denise Uzair, Ana Carla Castro Guijarro, Marina Inés Flamini, and Angel Matias Sanchez

Subjects
LH, cortactin, N-WASP, migration and invasion, breast cancer, Biology (General), QH301-705.5
Abstract

Breast cancer (BC) is a major public health problem affecting women worldwide. Approximately 80% of diagnosed cases are hormone-dependent breast cancers. These hormones are known to stimulate tumor development and progression. In this setting, tentative evidence suggests that luteinizing hormone (LH) may also play a role in tumors. In BC cells that express functional LH receptors (LHR), this hormone regulates cell migration and invasion by controlling several kinases that activate actin cytoskeletal proteins. In this article, we show that LH induces phosphorylation of paxillin and its translocation toward the plasmatic membrane, where focal adhesion complexes are assembled. This process is triggered via a rapid extra-gonadal LHR signaling to Src/FAK/paxillin, which results in the phosphorylation/activation of the nucleation promoter factors cortactin and N-WASP. As a consequence, Arp2/3 complexes induce actin polymerization, essential to promote cell adhesion, migration, and invasion, thus enhancing metastatic spread of tumoral cells. Our findings provide relevant information about how gonadotrophins exert their action in BC. This information helps us understand the extragonadal effects of LH on BC metastasis. It may provide new perspectives for therapeutic treatment, especially for women with high serum levels of gonadotrophins.

Published
2021
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5. Paxillin, a novel controller in the signaling of estrogen to FAK/N-WASP/Arp2/3 complex in breast cancer cells

Author

Jorge Eduardo Shortrede, Marina Inés Flamini, Angel Matías Sanchez, Flavia Judith Neira, and Ivonne Denise Uzair

Subjects
0301 basic medicine, Wiskott-Aldrich Syndrome Protein, Neuronal, Estrogen receptor, Arp2/3 complex, GTP-Binding Protein alpha Subunits, Gi-Go, Biochemistry, Endocrinology, Cell Movement, Phosphorylation, cdc42 GTP-Binding Protein, biology, Chemistry, GTP-Binding Protein beta Subunits, Bioquímica y Biología Molecular, Cell biology, Medicina Básica, Actin Cytoskeleton, Protein Transport, src-Family Kinases, Female, N-Wasp, biological phenomena, cell phenomena, and immunity, Signal Transduction, CIENCIAS MÉDICAS Y DE LA SALUD, PTK2, Breast Cancer Metastasis, Breast Neoplasms, macromolecular substances, Actin-Related Protein 2-3 Complex, Focal adhesion, 03 medical and health sciences, Cell Line, Tumor, Cell Adhesion, Humans, Neoplasm Invasiveness, Cell adhesion, Molecular Biology, Paxillin, Estrogen Receptor alpha, Estrogens, Actin cytoskeleton, Estrogen, 030104 developmental biology, Focal Adhesion Protein-Tyrosine Kinases, Raloxifene Hydrochloride, Cancer cell, Immunology, biology.protein, Raloxifene
Abstract

Breast cancer is the major cause of cancer-related death in women. Its treatment is particularly difficult when metastasis occurs. The ability of cancer cells to move and invade the surrounding environment is the basis of local and distant metastasis. Cancer cells are able to remodel the actin cytoskeleton, which requires the recruitment of numerous structural and regulatory proteins that modulate actin filaments dynamics, including Paxillin or the Neural Wiskott-Aldrich Syndrome Protein (N-WASP). We show that 17-β estradiol (E2) induces phosphorylation of Paxillin and its translocation toward membrane sites where focal adhesion complexes are assembled. This cascade is triggered by a Gαi1/Gβ protein-dependent signaling of estrogen receptor α (ERα) to c-Src, focal adhesion kinase (FAK) and Paxillin. Within this complex, activated Paxillin recruits the small GTPase Cdc42, which triggers N-WASP phosphorylation. This results in the redistribution of Arp2/3 complexes at sites where membrane structures related to cell movement are formed. Recruitment of Paxillin, Cdc42 and N-WASP is necessary for cell adhesion, migration and invasion induced by E2 in breast cancer cells. In parallel, we investigated whether Raloxifene (RAL), a selective estrogen receptor modulator (SERMs), could inhibit or revert the effects of E2 in breast cancer cell movement. We found that, in the presence of E2, RAL acts as an ER antagonist and displays an inhibitory effect on estrogen-promoted cell adhesion and migration via FAK/Paxillin/N-WASP. Our findings identify an original mechanism through which estrogen regulates breast cancer cell motility and invasion via Paxillin. These results may have clinical relevance for the development of new therapeutic strategies for cancer treatment. Fil: Shortrede, Jorge Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina Fil: Uzair, Ivonne Denise. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina Fil: Neira, Flavia Judith. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina Fil: Flamini, Marina Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina Fil: Sanchez, Angel Matias. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina

Published
2016
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6. Retinoic acid induces nuclear FAK translocation and reduces breast cancer cell adhesion through Moesin, FAK, and Paxillin

Author

Marina Inés Flamini, Angel Matías Sanchez, Jorge Eduardo Shortrede, and Laura M. Vargas-Roig

Subjects
0301 basic medicine, CIENCIAS MÉDICAS Y DE LA SALUD, Receptors, Retinoic Acid, Moesin, Retinoic Acid, HSP27 Heat-Shock Proteins, Retinoic acid, Breast Neoplasms, HSP72 Heat-Shock Proteins, Tretinoin, Biochemistry, Cell Adhesion/Migration, Phosphatidylinositol 3-Kinases, 03 medical and health sciences, chemistry.chemical_compound, Endocrinology, Cell Line, Tumor, Cell Adhesion, medicine, Humans, Breast Cancer Cells, Phosphorylation, Cell adhesion, Molecular Biology, Paxillin, Cell Nucleus, biology, Fak, Retinoic Acid Receptor alpha, Microfilament Proteins, Patología, Protein Transport, Retinoic acid receptor, Medicina Básica, src-Family Kinases, 030104 developmental biology, chemistry, Retinoic acid receptor alpha, Focal Adhesion Protein-Tyrosine Kinases, biology.protein, Cancer research, Female, Tumor Suppressor Protein p53, Signal transduction, Signal Transduction, medicine.drug
Abstract

Breast cancer is the most common malignancy in women, with metastases being the cause of death in 98%. In previous works we have demonstrated that retinoic acid (RA), the main retinoic acid receptor (RAR) ligand, is involved in the metastatic process by inhibiting migration through a reduced expression of the specific migration-related proteins Moesin, c-Src, and FAK. At present, our hypothesis is that RA also acts for short periods in a non-genomic action to cooperate with motility reduction and morphology of breast cancer cells. Here we identify that the administration of 10-6 M RA (10-20 min) induces the activation of the migration-related proteins Moesin, FAK, and Paxillin in T-47D breast cancer cells. The phosphorylation exerted by the selective agonists for RARα and RARβ, on Moesin, FAK, and Paxillin was comparable to the activation exerted by RA. The RARγ agonist only led to a weak activation, suggesting the involvement of RARα and RARβ in this pathway. We then treated the cells with different inhibitors that are involved in cell signaling to regulate the mechanisms of cell motility. RA failed to activate Moesin, FAK, and Paxillin in cells treated with Src inhibitor (PP2) and PI3K inhibitor (WM), suggesting the participation of Src-PI3K in this pathway. Treatment with 10-6 M RA for 20 min significantly decreased cell adhesion. However, when cells were treated with 10-6 M RA and FAK inhibitor, the RA did not significantly inhibit adhesion, suggesting a role of FAK in the adhesion inhibited by RA. By immunofluorescence and immunoblotting analysis we demonstrated that RA induced nuclear FAK translocation leading to a reduced cellular adhesion. These findings provide new information on the actions of RA for short periods. RA participates in cell adhesion and subsequent migration, modulating the relocation and activation of proteins involved in cell migration. Fil: Sanchez, Angel Matias. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina Fil: Shortrede, Jorge Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina Fil: Vargas Roig, Laura Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina Fil: Flamini, Marina Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina

Published
2016

7. Retinoic acid reduces migration of human breast cancer cells: role of retinoic acid receptor beta

Author

Gisel Valeria Gauna, Mayra Lis Sottile, Laura Maria Vargas-Roig, Marina Inés Flamini, Beatriz Silvina Nadin, and Angel Matías Sanchez

Subjects
BREAST CANCER CELLS, cell migration, Receptors, Retinoic Acid, Retinoic acid, Fluorescent Antibody Technique, Retinoic acid receptor beta, Apoptosis, CSK Tyrosine-Protein Kinase, Immunoenzyme Techniques, purl.org/becyt/ford/1 [https], chemistry.chemical_compound, Cell Movement, RETINOIC ACID, Tumor Cells, Cultured, retinoic acid, RNA, Small Interfering, Microfilament Proteins, Cell migration, Bioquímica y Biología Molecular, Actin Cytoskeleton, src-Family Kinases, Molecular Medicine, Female, CIENCIAS NATURALES Y EXACTAS, medicine.drug, Moesin, Blotting, Western, MOESIN, Antineoplastic Agents, Breast Neoplasms, Tretinoin, Biology, Ciencias Biológicas, Retinoids, medicine, Humans, purl.org/becyt/ford/1.6 [https], moesin, Cell Proliferation, RARβ, RAR BETA, FAK, Cell growth, Cell Biology, Original Articles, Molecular biology, Retinoic acid receptor, chemistry, CELL MIGRATION, Focal Adhesion Kinase 1, Cancer cell, Cancer research, breast cancer cells
Abstract

Breast cancer is the most common malignancy in women and the appearance of distant metastases produces the death in 98% of cases. The retinoic acid receptor b (RARb) is not expressed in 50% of invasive breast carcinoma compared with normal tissue and it has been associated with lymph node metastasis. Our hypothesis is that RARb protein participates in the metastatic process. T47D and MCF7 breast cancer cell lines were used to perform viability assay, immunobloting, migration assays, RNA interference and immunofluorescence. Administration of retinoic acid (RA) in breast cancer cells induced RARb gene expression that was greatest after 72 hrs with a concentration 1 lM. High concentrations of RA increased the expression of RARb causing an inhibition of the 60% in cell migration and significantly decreased the expression of migration-related proteins [moesin, c-Src and focal adhesion kinase (FAK)]. The treatment with RARa and RARc agonists did not affect the cell migration. On the contrary, the addition of the selective retinoid RARb-agonist (BMS453) significantly reduced cell migration comparable to RA inhibition. When RARb gene silencing was performed, the RA failed to significantly inhibit migration and resulted ineffective to reduce moesin,c-Src and FAK expressions. RARb is necessary to inhibit migration induced by RA in breast cancer cells modulating the expression of proteins involved in cell migration. Fil: Flamini, Marina Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina Fil: Gauna, Gisel Valeria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; Argentina Fil: Sottile Fleury, Mayra Lis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina Fil: Nadin, Silvina Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina Fil: Sanchez, Angel Matias. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina Fil: Vargas Roig, Laura Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina

Published
2014
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8. Molecular Actions of Thyroid Hormone on Breast Cancer Cell Migration and Invasion via Cortactin/N-WASP

Author

Ivonne Denise Uzair, Jeremias Conte Grand, Marina Ines Flamini, and Angel Matias Sanchez

Subjects
triiodothyronine, cortactin, N-WASP, cell motility and invasion, breast cancer, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

The thyroid hormone triiodothyronine (T3) plays a fundamental role in growth regulation, differentiation, metabolism and cellular movement. These processes are particularly important considering that deregulation of T3 levels could promote abnormal responsiveness of mammary epithelial cells, which may lead to the development and progression of breast cancer (BC). Once cells migrate and invade different tissues, BC metastasis is the main cause of cancer-related death because it is particularly difficult to revert this multistep process. Cell migration integrates several steps that induce changes in cell structure and morphology to promote BC cell invasion. These sequential steps include actin cytoskeleton remodeling, focal adhesion complex formation and, finally, the turnover of branched actin filament networks. In this article, we demonstrate that T3 has the ability to modify the Epithelial-Mesenchymal Transition process. In addition, we show that T3 induces actin cytoskeleton reorganization, triggers focal adhesion formation and, as a consequence, promotes actin nucleation via non-genomic pathway. These events are specifically modulated by T3 via integrin αvβ3 to FAK/paxillin/cortactin/N-WASP/Arp2/3 complex signaling pathway, increasing cell adhesion, migration and invasion of T-47D BC cells. We suggest that T3 influences the progression of tumor metastasis by controlling signaling pathways that converge in cell motility. This knowledge is crucial for the development of novel therapeutic strategies for BC treatment.

Published
2019
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9. Regulatory Actions of LH and Follicle-Stimulating Hormone on Breast Cancer Cells and Mammary Tumors in Rats

Author

Angel Matias Sanchez, Marina Ines Flamini, Sara Zullino, Eleonora Russo, Andrea Giannini, Paolo Mannella, Antonio Giuseppe Naccarato, Andrea Riccardo Genazzani, and Tommaso Simoncini

Subjects
LH, follicle stimulating hormone, moesin and focal adhesion kinase, cell motility, breast cancer, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

Gonadotrophins are mainly known to influence the body through the formation of gonadal steroids. However, receptors for luteinizing hormone (LH) and follicular-stimulating hormone (FSH) are present in a set of extra-gonadal tissues in humans and animals, but their functional relevance is uncertain. In this article, we present experimental evidence that, in T-47D breast cancer (BC) cells, FSH, and LH alter the expression of genes involved in adhesion, motility, and invasion through the activation of their receptors. Using miniarray technology we also found that LH influences the expression of a broad set of genes involved in cancer biology in T-47D cells. Interestingly, the regulatory actions of FSH and LH depend on the modality of exposure, with significant differences between pre-pubertal-like vs. post-menopausal-like amounts of gonadotrophins, but not after intermittent administration, representative of fertile life. We also studied the modulation of the circulating levels of gonadotrophins in an in vivo rat model of BC progression and observed a direct correlation with the extent of cancer growth. These results support the hypothesis that gonadotrophins may have direct effects on extra-gonadal tissues. They also highlight that gonadotrophins could potentially contribute to BC progression, particularly in post-menopausal women who typically have higher gonadotrophin levels. This research may ultimately lead to testing the use of gonadotrophin-modulating drugs in BC patients.

Published
2018
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