Could iodine be the missing micronutrient in breast cancer development?

Breast cancer is posing a serious threat to the health of the female workforce as one of the most prevalent malignancies. Emerging epidemiological evidence suggests that insufficient intake of the trace element, iodine, is associated with breast oncogenesis. In this paper, we propose a potential link between iodine deficiency and increased breast cancer risk. A central element of this mechanism may involve the cytoplasmic mislocalization and oncogenic function of the sodium/iodide symporter (NIS), which primarily mediates iodine transport under physiological conditions in the human body. We propose a three-stage model: (1) Initiation: Iodine deficiency triggers systemic alterations in the hypothalamic-pituitary-thyroid (HPT) and gonadal (HPG) axes, as well as lactogenic signaling, establishing a proliferative and inflamed breast microenvironment. (2) Heterogeneous subtype-specific evolution: For hormone receptor-positive (HR+) breast cancer, sustained PI3K/AKT activation driven by the relative dominance of estrogen disrupts normal glycosylation, leading to the cytoplasmic retention of NIS. For triple-negative breast cancer, and mutations primarily contribute to significant upregulation of NIS. (3) Malignant evolution: Cytoplasmic NIS associates with the leukemia-associated RhoA guanine exchange factor (LARG) and hyperactivates the RhoA-ROCK signaling pathway, driving cytoskeletal rearrangement, tumor invasion and metastasis. Deciphering the contributions of iodine status toward breast carcinoma development is assumed to open new avenues for novel therapeutic measures for breast cancer.