Abstract

Type 2 diabetes mellitus (T2DM) contributes significantly to the development and progression of cancers of the female reproductive tissues, particularly endometrial, ovarian, and breast. Hallmarks of T2DM, such as hyperinsulinemia, insulin resistance, and chronic low-grade inflammation, disrupt endocrine and metabolic homeostasis, promoting carcinogenesis through enhanced mitogenic signaling, hormonal dysregulation, and immune activation. T2DM can alter ovarian, endometrial, and mammary physiology by affecting estrogen/progesterone receptor activity, stromal remodeling, and specialized cell function. Furthermore, give the fluctuations in a woman's hormonal levels and reproductive status, the presence of excess weight and T2DM may have altering risks depending on the lifecycle. These effects are exacerbated by adipose-derived cytokines and leptin resistance, further amplifying estrogens' bioavailability and pro-inflammatory signaling. Endometrial cancer risk is nearly doubled in diabetic women, independent of body mass index, with hyperglycemia inducing PI3K/AKT/mTOR and NF-kappa B pathway activation, reduced sex hormone-binding globulin (SHBG) levels, and upregulation of estrogen receptor signaling. Ovarian cancer in diabetic patients is associated with more aggressive histological subtypes, advanced-stage presentation, and poorer survival, likely driven by Insulin-like growth factor 1 (IGF-1) signaling, oxidative stress, and impaired treatment response. Similarly, T2DM increases the risk and worsens outcomes in breast cancer via enhanced expression, AGE-RAGE interactions, and estrogen-independent ER alpha activation. Herein, we synthesize current epidemiological evidence and mechanistic insights to delineate the multifaceted relationship between T2DM and these cancers. Despite increased risk, diabetic women often face underdiagnosis due to suboptimal screening practices. As T2DM prevalence rises globally, tailored cancer prevention and treatment strategies for diabetic populations are urgently needed. Metformin has shown robust benefits in reducing T2DM-related complications and potential in the antineoplastic setting. This review underscores the endocrine and inflammatory mechanisms linking T2DM to cancers of the female reproductive system and advocates for integrated clinical protocols that include early screening and individualized management in diabetic women.