Abstract
Studies have suggested that type 2 diabetes (T2D) is associated with a higher incidence of breast cancer and related mortality rates. T2D postmenopausal women have an ~20% increased chance of developing breast cancer, and women with T2D and breast cancer have a 50% increase in mortality compared to breast cancer patients without diabetes. This correlation has been attributed to the general activation of insulin receptor signaling, glucose metabolism, phosphatidylinositol (PI) kinases, and growth pathways. Furthermore, the presence of breast cancer specific PI kinase and/or phosphatase mutations enhance metastatic breast cancer phenotypes. We hypothesized that each of the breast cancer subtypes may have characteristic PI phosphorylation profiles that are changed in T2D conditions. Therefore, we sought to characterize the PI phosphorylation when equilibrated in normal glycemic versus hyperglycemic serum conditions. Our results suggest that hyperglycemia leads to: 1) A reduction in PI3P and PIP3, with increased PI4P that is later converted to PI(3,4)P2 at the cell surface in hormone receptor positive breast cancer; 2) a reduction in PI3P and PI4P with increased PIP3 surface expression in human epidermal growth factor receptor 2-positive (HER2+) breast cancer; and 3) an increase in di- and tri-phosphorylated PIs due to turnover of PI3P in triple negative breast cancer. This study begins to describe some of the crucial changes in PIs that play a role in T2D related breast cancer incidence and metastasis.
Highlights
In the United States, over 276,480 new female cases of breast cancer are expected in 2020 alone [1]
The direct consequence of this higher than normal levels of INPP4B likely leads to the increased accumulation of PI3P, PI5P, and PI(3,5)P2 presumably generated from PI(3,4)P2, PI(4,5)P2, and PIP3, respectively
Based on the previously discussed metformin studies in triple negative breast cancer (TNBC), we had hypothesized that hyperglycemia would lead to a significant increase in di- and tri-phosphorylated PI content
Summary
In the United States, over 276,480 new female cases of breast cancer are expected in 2020 alone [1]. IDCs are molecularly subtyped as luminal (e.g., hormone responsive), human epidermal growth factor receptor 2-positive (HER2+), or basal-like (e.g., non-hormone) Though each of these IDC subtypes have distinct proliferative and invasive profiles, there are unifying trends in their glucose metabolism such as: (1) ~50% of cases across subtypes demonstrate perturbations in the insulin receptor signaling pathway during glucose metabolism and (2) type 2 diabetes (T2D) is a risk factor for the incidence of breast cancer and poorer outcomes [3,4,5,6,7,8]. Women with T2D were reported to have a 15%–20% [10] higher risk of being diagnosed with breast cancer and experience 30%–60% greater mortality than the general population [10] In understanding this phenomenon, several studies have proposed to define the pathophysiology of T2D, suggesting that T2D induces hyperinsulinemia which subsequently promotes estrogen receptor (ER) activity thereby promoting proliferation [11]. Greater ER activity promotes proliferative conditions in ER-dependent signaling pathways (i.e., insulin and estradiol) as well as downstream signaling pathways, such as PI3K/Akt in insulin, as well as subsequent growth pathways [11,12,13,14,15,16]
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