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，而且如果患上乳腺癌，她们的生存率也比非糖尿病女性更差。然而，需要更多的研究来阐明这些关系的生物学基础。在这里，我们发现叉头家族转录因子叉头盒 A1 (FOXA1) 和用于治疗 T2D 的药物二甲双胍（1,1-二甲基双胍盐酸盐）可能会影响激素受体阳性 (HR ) 乳腺癌 (BC ）肿瘤细胞的生长和转移。事实上，利用从 NCBI GEO 获得的 53,805 个基因数据库，14 个糖尿病相关基因仅在 3 个 HR 乳腺癌细胞系中高表达，而在其他亚型中则没有。在使用乳腺癌基因表达综合数据库收集的 4032 例乳腺癌患者组织样本中，糖尿病相关基因中，FOXA1、MTA3、PAK4、FGFR3 和 KIF22 在 HR 乳腺癌中高表达。值得注意的是，FOXA1 表达升高与雌激素受体阳性/孕激素受体阳性 (ER /PR ) 乳腺癌患者总体生存率较差相关。此外，实验表明，FOXA1 基因的缺失可在体外使用 MCF-7 和 T47D HR 乳腺癌细胞系抑制肿瘤增殖和侵袭。二甲双胍是一种抗糖尿病药物，可显着抑制 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 HR 乳腺癌细胞系中他莫昔芬诱导的肿瘤生长抑制。因此，糖尿病相关药物二甲双胍和FOXA1基因抑制与内分泌疗法他莫昔芬联合可能成为HR乳腺癌患者的新治疗方法。

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.