Hydrostatic pressure activates HIF-1α via β-catenin to promote stemness in breast cancer cells.

Tumor microenvironment plays a pivotal role in regulating the biological properties of cancer cells. Interstitial fluid hydrostatic pressure (HP) generally increases in malignant solid tumors. While our recent work has demonstrated that elevated HP stabilizes HIF-1α expression in cancer cells, here we further investigate whether elevated HP promotes cancer cells to acquire stemness features. Our results showed that exposure to 50 mmHg HP for 48 h did not significantly change the survival or morphology of human breast cancer cells. However, 50 mmHg HP stimulation significantly increased aldehyde dehydrogenase (ALDH) activity and upregulated HIF-1α and stemness markers (CD44 and SSEA-1) in MCF-7 and BT-474 but not in MDA-MB-453 breast cancer cell lines. Correspondingly, β-catenin was significantly enhanced in MCF-7 and BT-474 breast cancer cell lines under 50 mmHg HP stimulation and was negatively expressed in MDA-MB-453 breast cancer cells. Hypoxia (1% O2) exposure for 48 h also significantly enhanced the expression of β-catenin only in MCF-7 cells and BT-474 breast cancer cell lines, but increased HIF-1α expression and ALDH activity in all breast cancer cell lines tested, including the β-catenin-deficient MDA-MB-453 cells. Therefore, we conclude that elevated HP in malignant tumors may facilitate the acquisition of 'stemness' characteristics of cancer cells by enhancing HIF-1α expression via β-catenin.