These surprising results delineate a mechanism by which a transcription factor switches cells from ERK to p38 signaling in response to chemotherapy and suggest that therapeutic targeting of HIF1 or the p38 pathway in combination with chemotherapy will block BCSC enrichment and improve outcome in TNBC.<b>Significance:</b> These findings provide a molecular mechanism that may account for the increased relapse rate of women with TNBC who are treated with cytotoxic chemotherapy and suggest that combining chemotherapy with an inhibitor of HIF1 or p38 activity may increase patient survival.<i></i>.
To elucidate the role of the mammalian target of rapamycin (mTOR) signaling pathway in TNBC, the expression of molecules involved in mTOR signaling including mTOR, phosphorylated (p)-mTOR, p-4EBP1, GLUT1, GLUT3, HIF-1α, and Ki67 was investigated by immunohistochemistry in 35 TNBC and 81 non-TNBC cases.
Treatment of TNBC cell lines with dutasteride was associated with a dose-dependent decrease in cell viability, altered protein expression of VEGF and HIF-1α and increased chemosensitivity.