Abstract
BackgroundAdipokines, e.g. TNFα, IL-6 and leptin increase insulin resistance, and consequent hyperinsulinaemia influences breast cancer progression. Beside its mitogenic effects, insulin may influence adipokine production from adipocyte stromal cells and paracrine enhancement of breast cancer cell growth. In contrast, adiponectin, another adipokine is protective against breast cancer cell proliferation and insulin resistance.AMP-activated protein kinase (AMPK) activity has been found decreased in visceral adipose tissue of insulin-resistant patients. Lipopolysaccharides (LPS) link systemic inflammation to high fat diet-induced insulin resistance. Modulation of LPS-induced adipokine production by metformin and AMPK activation might represent an alternative way to treat both, insulin resistance and breast cancer.MethodsHuman preadipocytes obtained from surgical biopsies were expanded and differentiated in vitro into adipocytes, and incubated with siRNA targeting AMPKalpha1 (72 h), LPS (24 h, 100 μg/ml) and/or metformin (24 h, 1 mM) followed by mRNA extraction and analyses. Additionally, the supernatant of preadipocytes or derived-adipocytes in culture for 24 h was used as conditioned media to evaluate MCF-7 breast cancer cell proliferation.ResultsConditioned media from preadipocyte-derived adipocytes, but not from undifferentiated preadipocytes, increased MCF-7 cell proliferation (p < 0.01). Induction of IL-6 mRNA by LPS was reduced by metformin (p < 0.01), while the LPS-induced mRNA expression of the naturally occurring anti-inflammatory cytokine interleukin 1 receptor antagonist was increased (p < 0.01). Silencing of AMPKalpha1 enhanced LPS-induced IL-6 and IL-8 mRNA expression (p < 0.05).ConclusionsAdipocyte-secreted factors enhance breast cancer cell proliferation, while AMPK and metformin improve the LPS-induced adipokine imbalance. Possibly, AMPK activation may provide a new way not only to improve the obesity-related adipokine profile and insulin resistance, but also to prevent obesity-related breast cancer development and progression.
Highlights
Breast cancer is the most frequent cancer type among women worldwide, and 21% of all breast cancer deaths worldwide are estimated to be attributable to obesity and physical inactivity [1,2]
Conditioned medium (CM) from preadipocytes and preadipocyte-derived adipocytes (14 days after differentiation) was collected and breast cancer MCF-7 cell proliferation was evaluated after 72 h in these media (5 mM glucose) (Figure 1)
We silenced AMPKa1 subunit in preadipocyte-derived adipocytes to check its involvement in the effects of LPS on adipocytokine mRNA expression
Summary
Breast cancer is the most frequent cancer type among women worldwide, and 21% of all breast cancer deaths worldwide are estimated to be attributable to obesity and physical inactivity [1,2]. Invasive breast tumours break through the basement membrane and infiltrate fibrous tissue barriers, resulting in an immediate juxtaposition of adipocytes and breast cancer cells, allowing paracrine interactions between the two cell types [9]. Beside its stimulating effects on breast cancer cell proliferation [11], insulin may influence adipokine production from adipose tissue and adipocyte stromal cells and may indirectly reinforce cancer cell growth. Insulin may influence adipokine production from adipocyte stromal cells and paracrine enhancement of breast cancer cell growth. Adiponectin, another adipokine is protective against breast cancer cell proliferation and insulin resistance. Modulation of LPS-induced adipokine production by metformin and AMPK activation might represent an alternative way to treat both, insulin resistance and breast cancer
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