PDF(Pubmed)
Abstract：
Women with type 2 diabetes (T2D) have a higher risk of being diagnosed with breast cancer and have worse survival than non-diabetic women if they do develop breast cancer. However, more research is needed to elucidate the biological underpinnings of these relationships. Here, we found that forkhead box A1 (FOXA1), a forkhead family transcription factor, and metformin (1,1-dimethylbiguanide hydrochloride), a medication used to treat T2D, may impact hormone-receptor-positive (HR+) breast cancer (BC) tumor cell growth and metastasis. Indeed, fourteen diabetes-associated genes are highly expressed in only three HR+ breast cancer cell lines but not the other subtypes utilizing a 53,805 gene database obtained from NCBI GEO. Among the diabetes-related genes, FOXA1, MTA3, PAK4, FGFR3, and KIF22 were highly expressed in HR+ breast cancer from 4032 breast cancer patient tissue samples using the Breast Cancer Gene Expression Omnibus. Notably, elevated FOXA1 expression correlated with poorer overall survival in patients with estrogen-receptor-positive/progesterone-receptor-positive (ER+/PR+) breast cancer. Furthermore, experiments demonstrated that loss of the FOXA1 gene inhibited tumor proliferation and invasion in vitro using MCF-7 and T47D HR+ breast cancer cell lines. Metformin, an anti-diabetic medication, significantly suppressed tumor cell growth in MCF-7 cells. Additionally, either metformin treatment or FOXA1 gene deletion enhanced tamoxifen-induced tumor growth inhibition in HR+ breast cancer cell lines within an ex vivo three-dimensional (3D) organoid model. Therefore, the diabetes-related medicine metformin and FOXA1 gene inhibition might be a new treatment for patients with HR+ breast cancer when combined with tamoxifen, an endocrine therapy.
摘要：
患有2型糖尿病（T2D）的女性被诊断出患有乳腺癌的风险更高，并且与非糖尿病女性相比，如果她们确实患有乳腺癌，则生存率更差。然而,需要更多的研究来阐明这些关系的生物学基础。这里,我们发现叉头盒A1(FOXA1)，叉头家族转录因子，和二甲双胍（1,1-二甲基双胍盐酸盐），一种用于治疗T2D的药物，可能影响激素受体阳性（HR+）乳腺癌（BC）肿瘤细胞的生长和转移。的确,利用从NCBIGEO获得的53,805基因数据库，仅在三种HR乳腺癌细胞系中高度表达了14种与糖尿病相关的基因，而在其他亚型中却没有。在与糖尿病相关的基因中，FOXA1、MTA3、PAK4、FGFR3和KIF22在来自4032个乳腺癌患者组织样品的HR+乳腺癌中使用乳腺癌基因表达综合表达。值得注意的是,在雌激素受体阳性/孕激素受体阳性(ER+/PR+)乳腺癌患者中,FOXA1表达升高与总生存期较差相关.此外，实验表明，使用MCF-7和T47DHR乳腺癌细胞系，FOXA1基因的丢失在体外抑制了肿瘤的增殖和侵袭。二甲双胍,抗糖尿病药物，显著抑制MCF-7细胞中肿瘤细胞的生长。此外,在离体三维（3D）类器官模型中，二甲双胍治疗或FOXA1基因缺失增强了他莫昔芬诱导的HR乳腺癌细胞系中肿瘤生长抑制。因此,糖尿病相关药物二甲双胍和FOXA1基因抑制可能是HR+乳腺癌患者联合他莫昔芬治疗的新方法，内分泌疗法.
