How does metabolic reprogramming in type 2 diabetes affect breast cancer biology, and can metformin reverse it through AMPK/mTOR and RNA interactions? Breast cancer is a common cancer in women. Aggressive subtypes like triple-negative breast cancer (TNBC) lack targeted treatments, leading to poor prognosis and underscoring the critical need for novel treatment strategies. Recent study suggests that Patient with type 2 diabetes has higher risk to get metabolic cancer compared to people without type 2 diabetes. 15% of patients have breast cancer and T2D simultaneously. This shows the lowering-glucose effects of metformin or other andiabetic drugs have potential to treat breast cancer and increase cancer outcomes (12). Metformin is recommended due to its low price, high efficacy, weigh neutrality and safety (2), (10). These observations are promising but the precise mechanism of metformin is not fully elucidated (8). Metformin, a first-line biguanide drug which commonly used to treat type 2 diabetes worldwide. As a member of guanidine, it was derived from plant Galega officinalis or French lilac. The antihyperglycaemic action of metformin was first used in 1957 in Europe and used in USA since 1994 (2). Metformin inhibits the hepatic gluconeogenesis, thereby reducing the glucose level and insulin production. According to UKPDS (United Kingdom Prospective Diabetes Study), metformin has the effect to reduce macrovascular complications (2). Moreover, metformin work on inflammatory marker and weigh loss (7). The inconsistent metformin dose among reviews is a reason that slower down the metformin used. The research of AMPK pathway due to complex I inhibition have only been found in the context of supra-pharmacological (>1 mM) metformin doses, which do not exist in the clinical setting (8). Metformin primary target at mitochondrion, where it blocks mitochondrial complex I, decreasing in ATP production and inducing energy stress (6). The elevated AMP/ADP might drive two main pathways: the inhibition of cAMP synthesis, reducing glucagon signalling and the activation of 5-AMP-activated protein kinase (AMPK), which promotes insulin sensitivity and metabolism regulation. AMPK triggers catabolic (ATP-producing) and inhibits biosynthetic pathways (ATP-consuming). AMPK activation causes directly or indirectly effects to tumour cell growth and proliferation (10), (2). Directly, within cancer cells, AMPK inhibits regulator of lipid synthesis, mTORC1. The mTORC1 is a nutrition and growth factor in several biosynthetic development such as protein translation. In lipid metabolism, metformin can improve the insulin sensitivity by activating AMPK reduces the accumulation of lipid and improve insulin receptor signalling (8), (10). There is another downstream pathway of AMPK inhibits the acetyl-CoA carboxylase (ACC), a rate-limiting enzyme in lipogenesis and increases lipid oxidation, suggesting that metformin could fundamentally reprogram tumour lipid, converting it from synthesis driven state to catabolic- driven state. Less ATP and insufficient building blocks such as fatty acid for cell membrane formed, tumour cells cannot support their growth and proliferation (8), (2) On the other hands, AMPK have Indirectly anti-cancer effect at the organism level. Metformin's AMPK-mediated suppression of hepatic gluconeogenesis which improves systemic insulin sensitivity and reduces circulating circulating levels of tumor-promoting growth factors like insulin and IGF-1. AMPK is a key node to coordinate cell metabolism with particular energy demands. Tumour cells frequently exhibit oncogenically unregulated AKT, which phosphorylates AMPK. Metformin has antitumourgenesis effect in breast cancer by fundamentally reprogramming in lipid metabolism (6). Beyond these metabolic pathways, metformin exerts its anti-cancer effects though RNA interaction. The interaction of RNAs turn the regulating gene expression and cellular process (11). 70% BC cases are sporadic, meaning that it causes by lifestyle, random mutation in cells and environmental factors. About 30% breast cancer are hereditary. Familiar breast cancer triggered by different level of penetrance in susceptibility genes. High penetrates genes such as BRCA1, BRCA2, TP53 involved in 22 percent in familial BC. BRCA1 and BRCA2 are the most well known high penetrate gene associated with hereditary breast cancer, particularly in TNBC and other subtypes. As the tumour suppresses genes, they repair DNA double-strand break. BC with BRCA1/2 mutation are deficient in Homologous Recombination (HR) (1). We hypothesise that metformin can solve this vulnerability by upregulating specific microRNAs (e.g., miR-182) that target the mRNA of BRCA1 (3). Thus, creating a synthetic lethal vulnerability in BRCA-deficient breast cancer cells. Furthermore, HER2(ERBB2) is a somatic oncogene of breast cancer which is a member of epidermal growth factor receptor (EGFR) family, plays critical role in mammary cell proliferation and survival. HER2 protein overexpression present in 20-30% of breast carcinomas. It is able to trigger downstream signalling and activates the growth and proliferation of cell. The anti-cancer effect of metformin on breast cancer though HER2 pathway was proved in recent study using breast cancer cell line SK-BR-3 that has over-expression of HER2. The over-expression of HER2 will result in Akt signalling that promotes cell survival and growth (4). Type 2 diabetes is a metabolic disease with severals systemic complications, is a risk factor of other diseases. Dsyregulation of glucose pathway might cause problem in lots of downstream pathways such as protein synthesis and lipid metabolism. For example, defeated glucose metabolism causes accumulation of fatty acids, contributing to condition like obesity. The intervention drugs of glucose metabolism is a good choice to mitigate several complications beyond diabetes. Metformin is a drug to treat type 2 diabetes by lowering the glucose level. Given that glucose is a primary source for cell growth and proliferation, its abundance can support the rapid division of cells, including tumor cell (2). Metformin activates the AMPK, a cellular energy sensor and metabolic regulator. As a key signaling node, AMPK allows cells to coordinate their metabolism in response to energy demands (6). Breast cancer is a common cancer affecting women. Its development can be driven by various genetic defeated, which are divided into inherited (familial) mutations or somatic mutations. High-penetrance susceptibility genes like BRCA1 and BRCA2 account for a significant proportion of familial breast cancer cases, while somatic overexpression of the HER2 has high percentages involved in breast carcinomas. We aimed to reveal the intervention of metformin to reduces the probability of breast cancer through AMPK/mTOR metabolic reprogramming and RNA interaction of HR deficiency and HER2 signaling. We will specifically assess the impact of metformin on the mRNA expression levels of BRCA1/2 and HER2 to elucidate these novel mechanisms