Gap junctional intercellular communication (GJIC) is a homeostatic process mediated by membrane channels composed of a protein family known as connexins. Alterations to channel activity can modulate suppression or facilitation of cancer progression. These varying roles are influenced by the cancer cell genetic profile and the context-dependent mechanisms of a dynamic extracellular environment that encompasses fluctuations to nutrient availability. To better explore the effects of altered cellular metabolism on GJIC in breast cancer, we generated a derivative of the triple-negative breast cancer cell line MDA-MB-231 optimized for growth in low-glucose. Reduced availability of glucose is commonly encountered during tumor development and leads to metabolic reprogramming in cancer cells. MDA-MB-231 low-glucose adapted cells exhibited a larger size with improved cell–cell contact and upregulation of cadherin-11. Additionally, increased protein levels of connexin 43 and greater plasma membrane localization were observed with a corresponding improvement in GJIC activity compared to the parental cell line. Since GJIC has been shown to affect cellular invasion in multiple cancer cell types, we evaluated the invasive qualities of these cells using multiple three-dimensional Matrigel growth models. Results of these experiments demonstrated a significantly more invasive phenotype. Moreover, a decrease in invasion was noted when GJIC was inhibited. Our results indicate a potential response of triple-negative breast cancer cells to reduced glucose availability that results in changes to GJIC and invasiveness. Delineation of this relationship may help elucidate mechanisms by which altered cancer cell metabolism affects GJIC and how cancer cells respond to nutrient availability in this regard.

间隙连接细胞间通讯（GJIC）是由膜通道介导的体内平衡过程，该膜通道由称为连接蛋白的蛋白质家族组成。通道活性的改变可以调节癌症进展的抑制或促进。这些不同的作用受癌细胞遗传特征和动态细胞外环境（取决于养分利用率波动）的背景相关机制的影响。为了更好地探索乳腺癌中细胞代谢改变对GJIC的影响，我们生成了三阴性乳腺癌细胞系MDA-MB-231的衍生物，该衍生物针对低葡萄糖生长进行了优化。葡萄糖的可利用性降低通常在肿瘤发展期间遇到，并导致癌细胞中的代谢重编程。MDA-MB-231低葡萄糖适应性细胞具有更大的尺寸，并改善了细胞间的接触并上调了钙黏着蛋白11。此外，与亲本细胞系相比，观察到连接蛋白43的蛋白水平增加和更大的质膜定位，GJIC活性相应提高。由于已显示GJIC可影响多种癌细胞类型的细胞浸润，因此我们使用多个三维Matrigel生长模型评估了这些细胞的浸润特性。这些实验的结果证明了明显更具侵袭性的表型。而且，当抑制GJIC时，注意到侵袭的减少。我们的结果表明，三阴性乳腺癌细胞对降低葡萄糖利用率的潜在反应可能导致GJIC和侵袭性的改变。