Metformin Prevents Tumor Cell Growth and Invasion of Human Hormone Receptor-Positive Breast Cancer (HR+ BC) Cells via FOXA1 Inhibition.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Hepatocyte Nuclear Factor 3-alpha*/metabolism ; Hepatocyte Nuclear Factor 3-alpha*/genetics ; Metformin*/pharmacology ; Breast Neoplasms*/drug therapy ; Breast Neoplasms*/metabolism ; Breast Neoplasms*/pathology ; Breast Neoplasms*/genetics ; Cell Proliferation*/drug effects; Humans ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Cell Line, Tumor ; Receptors, Estrogen/metabolism ; Receptors, Estrogen/genetics ; Neoplasm Invasiveness ; MCF-7 Cells ; Receptors, Progesterone/metabolism ; Receptors, Progesterone/genetics

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.

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Keywords: forkhead box A1 (FOXA1); hormone-receptor-positive (HR+) breast cancer (BC); metastasis; metformin; tumor proliferation; type 2 diabetes (T2D)

0 (Hepatocyte Nuclear Factor 3-alpha)
9100L32L2N (Metformin)
0 (FOXA1 protein, human)
0 (Receptors, Estrogen)
0 (Receptors, Progesterone)

Date Created: 20240713 Date Completed: 20240713 Latest Revision: 20240715

20250114

PMC11242876

10.3390/ijms25137494

39000600