OR16-05 25-Hydroxycholesterol Mediates The Effects Of Dyslipidemia On Triple Negative Breast Cancer Metastasis
Authors: Etella Abora , Scully Tiffany , Jordan Stefan , Kang Chifei , Jeffrey McDonald G , Kase Nathan G , LeRoith Derek , Gallagher Emily J 
Published: October 2023

Disclosure: A. Etella: None. T. Scully: None. S. Jordan: None. C. Kang: None. M.G. Jeffrey: None. N.G. Kase: None. D. LeRoith: None. E.J. Gallagher: Advisory Board Member; Self; Novartis Pharmaceuticals. Consulting Fee; Self; Seagen, Flare Therapeutics.

Excess body weight and dyslipdemia have been associated with reduced disease-free, and overall survival in women with triple negative breast cancer (TNBC). TNBC does not express hormone (estrogen or progesterone) receptors, or overexpress human epidermal growth factor receptor (HER2) and accounts for 10-20% of breast cancers globally, although amongst some populations (e.g. Black women in the US) the rates are higher. The mechanisms linking dyslipidemia and TNBC outcomes are not well understood. To study the mechanisms involved, we injected murine (Mvt1) or human (MDA-MB-231) TNBC cells into the inguinal fat pad of immunocompetent or immunodeficient dyslipidemic apolipoprotein E knockout (ApoE-/-) mice and respective controls. Tumors grew larger and developed more metastasis in the ApoE-/- mice compared with controls. We examined the oxysterol content of the tumors and found higher concentrations of 25-hydroxycholesterol (25-OHC) in the Mvt1 tumors from ApoE-/- mice compared with controls (2.05±0.8ng/mg vs 0.33±0.09ng/mg, P=0.048, n=6 per group). Similarly concentrations were higher in the MDA-MB-231 tumors from immunocompromised ApoE-/- mice compared with controls (0.06±0.007ng/mg vs 0.002±0.004ng/mg, P=0.008, n=6 per group). To explore the importance of 25-OHC in TNBC growth and metastasis, we used the cholesterol 25 hydroxylase knockout (Ch25h-/-) mice on the C57BL/6 background and backcrossed the mice to the FVB/n background. In the C57BL/6 Ch25h-/- and control mice, we injected M-Wnt cells into the inguinal fat pad. We found no difference in primary tumor growth, but significantly fewer metastases (mets) in the lungs in the Ch25h-/- mice compared with controls (1.7±1.1 vs 15.3±6.7 mets/mouse, P&lt;0.01). Similarly no difference in primary tumor size was observed between groups in the FVB/n mice, but the Ch25h-/- mice again had fewer lung metastases compared with controls (6.0±0.9 vs 14.5±2.1 mets/mouse, P&lt;0.01, n=8-9 per group). The M-Wnt and Mvt1tumor cells did not express significant levels of Ch25h; however, high levels of CH25H have been observed in macrophages in the breast. In vitro, we found that 25-OHC stimulation of macrophages induced the secretion chemokines IL8, CCL3, CCL4, and increased the migration of human MDA-MB-231 and MDA-MB-468 breast cancer cells. The expression of these chemokines was found to be &gt;50% lower in the M-Wnt and Mvt1 tumors from the Ch25h-/- mice compared with controls. These results show that the 25-OHC in the tumor microenvironment plays an important role in TNBC metastasis and may be an important mechanism linking dyslipidemia with poor TNBC survival.

Presentation: Friday, June 16, 2023