Micro- and nano-plastics (MNPs) are debris generated from the fragmentation of larger plastic particles. Due to their pervasive and persistent nature, MNPs - accumulated in the environment and widespread distributed across diverse ecosystems - have been detected in human blood, tissues and cells. Once considered as biologically inert, MNPs are emerging as cellular stressors with acknowledged biological properties, leading to diverse physio-pathological responses. Herein, we present the most recent findings regarding the actions of MNPs as endocrine disruptors, emphasizing the novel findings suggestive of a potential stimulatory role played by these environmental pollutants in hormone-related cancers. In this vein, we provide a critical overview of the molecular mechanisms and the metabolic pathways activated by MNPs and implicated in the disruption of hormone/hormone receptor signaling, possibly leading to cancer progression. Next, we highlight the main areas of knowledge gap in the field, suggesting novel approaches that may allow a better understanding of environmental MNPs' action in human diseases. Considering the escalating environmental exposure to MNPs envisaged for the next years, irrespective of any counteractive measure, our comprehensive and detailed analysis contributes to a better evaluation of the endocrine effects associated with these emergent environmental pollutants. Our work corroborates research efforts worldwide, helping to build and expand knowledge on the endocrine effects elicited by MNPs, also in hormone-related cancers.

Obesity is frequently associated with metabolic alterations like hypercholesterolemia and hyperinsulinemia and represents a major risk factor for several diseases, including breast cancer (BC). Insulin signaling, as well as the frequent overexpression of the insulin receptor (IR), play a key role in BC progression. Emerging evidence suggests that the widely prescribed lipid-lowering drugs, named statins, may reduce the risk of recurrence and blunt BC cell proliferation, mainly inhibiting the HMGCR-dependent activation of the mevalonate pathway. In this study, we investigated the effects of simvastatin, atorvastatin and rosuvastatin in BC cells stimulated by insulin. To this end, we used as a BC model system MCF7 cells and naturally immortalized BCAHC-1 cells, which are characterized by high IR-expression levels. Our investigation demonstrates that statins reduce the proliferation and clonogenic capacity of BC cells prompted by insulin treatment. Mechanistically, statins impair the IR-mediated signaling and downregulate the stress-inducible transcription factor NUPR1, a known regulator of cancer progression. Importantly, NUPR1 inhibition blunted the stimulatory action of insulin on BC cells. Consistent with these findings, survival analyses of large cohorts of patients revealed that high levels of NUPR1 are associated with poor BC prognosis. Overall, our results provide novel mechanistic evidence supporting the repositioning of statins in BC, particularly in tumors characterized by elevated IR expression and activity.