scholarly journals Osteocytic Connexin Hemichannels Modulate Oxidative Bone Microenvironment and Breast Cancer Growth

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6343
Author(s):  
Yi Tian ◽  
Manuel A. Riquelme ◽  
Chao Tu ◽  
Yumeng Quan ◽  
Xiaowen Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Gap Junctions ◽  
Cancer Cells ◽  
Connexin 43 ◽  
Breast Cancer Cells ◽  
Dominant Negative ◽  
Cancer Growth ◽  
Breast Cancer Growth

Osteocytes, the most abundant bone cell types embedded in the mineral matrix, express connexin 43 (Cx43) hemichannels that play important roles in bone remodeling and osteocyte survival. Estrogen deficiency decreases osteocytic Cx43 hemichannel activity and causes a loss in osteocytes’ resistance to oxidative stress (OS). In this study, we showed that OS reduced the growth of both human (MDA-MB-231) and murine (Py8119) breast cancer cells. However, co-culturing these cells with osteocytes reduced the inhibitory effect of OS on breast cancer cells, and this effect was ablated by the inhibition of Cx43 hemichannels. Py8119 cells were intratibially implanted in the bone marrow of ovariectomized (OVX) mice to determine the role of osteocytic Cx43 hemichannels in breast cancer bone metastasis in response to OS. Two transgenic mice overexpressing dominant-negative Cx43 mutants, R76W and Δ130-136, were adopted for this study; the former inhibits gap junctions while the latter inhibits gap junctions and hemichannels. Under normal conditions, Δ130-136 mice had significantly more tumor growth in bone than that in WT and R76W mice. OVX increased tumor growth in R76W but had no significant effect on WT mice. In contrast, OVX reduced tumor growth in Δ130-136 mice. To confirm the role of OS, WT and Δ130-136 mice were administered the antioxidant N-acetyl cysteine (NAC). NAC increased tumor burden and growth in Δ130-136 mice but not in WT mice. Together, the data suggest that osteocytes and Cx43 hemichannels play pivotal roles in modulating the oxidative microenvironment and breast cancer growth in the bone.

Paradoxical Hormone Responses of KPL-1 Breast Cancer Cells in vivo: A Significant Role of Angiogenesis in Tumor Growth

Oncology ◽  
2000 ◽  
Vol 59 (2) ◽  
pp. 158-165 ◽  
Author(s):  
Junichi Kurebayashi ◽  
Hironori Kunisue ◽  
Shigeru Yamamoto ◽  
Masafumi Kurosumi ◽  
Takemi Otsuki ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Significant Role ◽  
Breast Cancer Cells ◽  
Hormone Responses

Abstract 246: Translocation Of Myomirs Via Gap Junction Channels Prevents Cancer Cell Growth

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Laura Graciotti ◽  
Toru Hosoda ◽  
Marcello Rota ◽  
Giulia Borghetti ◽  
Sergio Signore ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gap Junctions ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Connexin 43 ◽  
Breast Cancer Cells ◽  
Fold Increase ◽  
Tumor Formation

The adult heart is resistant to cancer formation and the metastatic invasion of distant neoplasms. This biological advantage may be dictated by the molecular properties of myocytes that constitutes 90% of the myocardium. We raised the possibility that microRNAs (miRs) highly expressed in myocytes (myomirs) may translocate via gap junctions to neighboring cancer cells, preventing their growth or inhibiting their survival. First, we established whether overexpression of myomirs interferes with the proliferation and death of MCF7 human breast cancer cells. Infection of MCF7 with lentiviruses carrying miR-1, miR-133a and miR-499 (miR-MCF7) resulted in a 5-fold decrease in Ki67 labeling and a 20% increase in the fraction of cells arrested at G0/G1. In contrast, TdT-positive apoptotic cells averaged 0.5% and did not differ in miR-MCF7 and control cells. To mimic the in vivo condition, EGFP-labeled MCF7 were co-cultured with myocytes and, 4 days later, the expression of myomirs was measured in FACS-sorted MCF7. With respect to baseline, co-cultured MCF7 showed 100-fold, 16-fold, and 27-fold increase in the expression of miR-1, miR-133a and miR-499, respectively. Co-culture of myocytes and MCF7 led to the formation of gap junctions made of connexin 43 (Cx43) and connexin 45 (Cx45). Silencing of Cx43 and Cx45 decreased significantly the expression of myomirs in co-cultured MCF7. Importantly, proximity of MCF7 to myocytes reduced markedly the growth rate of the cancer cells. Subsequently, 1 x 106 MCF7 or miR-MCF7 were injected subcutaneously in NOD-scid mice. At 5 weeks, the tumors developed from miR-MCF7 were 70% smaller than those originated from control MCF7. Two doses of breast cancer cells were injected intramyocardially to establish their in situ tumorigenic effects. Tumor formation was found in all hearts that received 1 x 106 MCF7. Conversely, mice injected with 1 x 105 cells did not show macroscopic evidence of neoplastic lesions. The lack of tumor development in the latter case is consistent with the ability of the heart to prevent neoplasm development when cancer cell colonization is not massive. Our findings document that miR-1, miR-133a and miR-499 translocate from myocytes to cancer cells via gap junctions, inhibiting tumor growth in vitro and in vivo.

scholarly journals Leader cell activity and collective invasion by an autocrine nucleotide loop through connexin-43 hemichannels and ADORA1

2019 ◽  
Author(s):  
Antoine A. Khalil ◽  
Olga Ilina ◽  
Angela Vasaturo ◽  
Jan-Hendrik Venhuizen ◽  
Manon Vullings ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gap Junctions ◽  
Cancer Cells ◽  
Connexin 43 ◽  
Breast Cancer Cells ◽  
Cell Activity ◽  
Collective Invasion ◽  
Leader Cell ◽  
Adenosine Nucleotide

AbstractProgression of epithelial cancers predominantly proceeds by collective invasion of cell groups with coordinated cell-cell junctions and multicellular cytoskeletal activity. Collectively invading breast cancer cells co-express adherens junctions and connexin-43 (Cx43) gap junctions in vitro and in patient samples, yet whether gap junctions contribute to collective invasion remains unclear. We here show that Cx43 is required for chemical coupling between collectively invading breast cancer cells and, by its hemichannel function, adenosine nucleotide release into the extracellular space. Using molecular interference and rescue strategies in vitro and in orthotopic mammary tumors in vivo, Cx43-dependent adenosine nucleotide release was identified as essential mediator engaging the nucleoside receptor ADORA1, to induce leader cell activity and collective migration. In clinical samples joint-upregulation of Cx43 and ADORA1 predicts decreased relapse-free survival. This identifies autocrine nucleotide signaling, through a Cx43/ADORA1 axis, as critical pathway in leader cell function and collective cancer cell invasion.Graphical abstract

scholarly journals Tumor cell-adipocyte gap junctions activate lipolysis and are essential for breast tumorigenesis

2018 ◽  
Author(s):  
Roman Camarda ◽  
Jeremy Williams ◽  
Serghei Malkov ◽  
Lisa J. Zimmerman ◽  
Suzanne Manning ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Gap Junctions ◽  
Gap Junction ◽  
Cancer Cells ◽  
Breast Tumor ◽  
Breast Cancer Cells ◽  
Molecular Mechanisms ◽  
Dependent Manner

AbstractDuring tumorigenesis, a heterotypic interface exists between cancer and stromal cells that can both support and repress tumor growth. In the breast, studies have demonstrated a pro-tumorigenic role for adipocytes. However, the molecular mechanisms by which breast cancer cells coopt adipocytes remain elusive. Studying breast tumors and normal adjacent tissue (NAT) from several patient cohorts and mouse models, we show that lipolysis and lipolytic signaling are activated in NAT. We investigate the tumor-adipocyte interface and find that functional gap junctions form between breast cancer cells and adipocytes. As a result, cAMP, a critical lipolysis-inducing signaling molecule, is transferred from breast cancer cells to adipocytes and activates lipolysis in a gap junction-dependent manner; a fundamentally new mechanism of lipolysis activation in adipocytes. We find that gap junction formation depends upon connexin 31 (Cx31), and that Cx31 is essential for breast tumor growth and activation of lipolysis in vivo. Thus, direct tumor cell-adipocyte interaction is critical for tumorigenesis and may serve as a new therapeutic target in breast cancer.One sentence summaryGap junctions between breast cancer cells and adipocytes transfer cAMP and activate lipolysis in the breast tumor microenvironment.

scholarly journals Inflammatory conversion of quiescent osteoblasts by metastatic breast cancer cells through pERK1/2 aggravates cancer-induced bone destruction

Bone Research ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Jungho Back ◽  
Minh Nam Nguyen ◽  
Lu Li ◽  
Saelim Lee ◽  
Inkyu Lee ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Bone Destruction ◽  
Metastatic Breast ◽  
Mek Inhibitor ◽  
Dominant Negative ◽  
Cancer Growth ◽  
Breast Cancers ◽  
Bone Homeostasis

AbstractDisruption of bone homeostasis caused by metastatic osteolytic breast cancer cells increases inflammatory osteolysis and decreases bone formation, thereby predisposing patients to pathological fracture and cancer growth. Alteration of osteoblast function induces skeletal diseases due to the disruption of bone homeostasis. We observed increased activation of pERK1/2 in osteolytic breast cancer cells and osteoblasts in human pathological specimens with aggressive osteolytic breast cancer metastases. We confirmed that osteolytic breast cancers with high expression of pERK1/2 disrupt bone homeostasis via osteoblastic ERK1/2 activation at the bone-breast cancer interface. The process of inflammatory osteolysis modulates ERK1/2 activation in osteoblasts and breast cancer cells through dominant-negative MEK1 expression and constitutively active MEK1 expression to promote cancer growth within bone. Trametinib, an FDA-approved MEK inhibitor, not only reduced breast cancer-induced bone destruction but also dramatically reduced cancer growth in bone by inhibiting the inflammatory skeletal microenvironment. Taken together, these findings suggest that ERK1/2 activation in both breast cancer cells and osteoblasts is required for osteolytic breast cancer-induced inflammatory osteolysis and that ERK1/2 pathway inhibitors may represent a promising adjuvant therapy for patients with aggressive osteolytic breast cancers by altering the shared cancer and bone microenvironment.

scholarly journals p42/p44 MAPK-mediated Stat3Ser727 phosphorylation is required for progestin-induced full activation of Stat3 and breast cancer growth

2013 ◽  
Vol 20 (2) ◽  
pp. 197-212 ◽  
Author(s):  
Mercedes Tkach ◽  
Cinthia Rosemblit ◽  
Martín A Rivas ◽  
Cecilia J Proietti ◽  
María Celeste Díaz Flaqué ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cyclin D1 ◽  
Cancer Cells ◽  
Transcriptional Activation ◽  
Breast Cancer Cells ◽  
Receptor Expression ◽  
Cancer Growth ◽  
Stat3 Phosphorylation ◽  
Breast Cancer Growth

Stat3 is a signaling node for multiple oncogenic pathways and is therefore frequently active in breast cancer. As experimental and clinical evidence reveals that progestins are key players in controlling mammary gland tumorigenesis, we studied Stat3 participation in this event. We have previously shown that progestins induce Stat3Tyr705 phosphorylation and its transcriptional activation in breast cancer cells. In this study, we demonstrate that progestins also induce Stat3 phosphorylation at Ser727 residue, which occurs via activation of c-Src/p42/p44 MAPK pathways in murine progestin-dependent C4HD cells and in T-47D cells. Expression of a Stat3S727A vector, which carries a serine-to-alanine substitution at codon 727, shows that Stat3Ser727 phosphorylation is required for full transcriptional activation of cyclin D1 gene expression by progestins and for in vivo Stat3 recruitment on cyclin D1 promoter. Transfection of Stat3S727A in murine and human breast cancer cells abolished progestin-induced in vitro and in vivo growth. Moreover, we found a positive correlation between progesterone receptor expression and nuclear localization of Stat3Ser727 phosphorylation in breast cancer biopsies. These data highlight Stat3 phosphorylation in Ser727 residue as a nongenomic action by progestins, necessary to promote breast cancer growth.

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