Mutual regulation of HIF-1 and PKM2 in glucose reprogramming.

Breast cancer is the leading cause of cancer-related death in women. Despite significant advances in treatment of breast cancer, breast cancer metastasis remains the ultimate challenge and causes about 90 percent of deaths due to breast cancer. Understanding breast cancer metastasis would improve breast cancer therapy and greatly benefit individuals and society.

Intratumoral hypoxia is the featured microenvironment of breast tumor, and induces activation of Hypoxia-Inducible Factor 1 (HIF-1), which is one of most important driving forces of breast cancer metastasis. HIF-1 is a heterodimeric transcription factor, consisting of HIF-1α and HIF-1β subunits. HIF-1α is overexpressed in primary breast tumor biopsies and high HIF-1α levels in breast tumors are significantly associated with poor prognosis and increased mortality of breast cancer patients. Thus, HIF-1 has been appreciated as an important target for breast cancer therapy.

HIF-1 activates transcription of over 1000 target genes, whose protein products promote tumor growth, invasion, and metastasis by regulating the key pathways in cancer cells, including metabolism (Figure 1) and epigenetics (Figure 2).

Mutual regulation of HIF-1 and JMJD2C in breast cancer metastasis.

Breast cancer metastasis is often accompanied by epigenetic and metabolic alterations. However, how epigenetic or metabolic alterations regulate HIF-1 activity to promote breast cancer metastasis is largely unknown, and how HIF-1 induces epigenetic or metabolic changes to promote breast cancer metastasis is not fully understood. Particularly, how metabolism-epigenetics crosstalk regulates HIF-1 activity is a puzzle.

The central theme of the lab's research is to understand, at the molecular and cellular levels, the role of HIF-1 in breast cancer metastasis with particular focuses on crosstalk of HIF-1, epigenetics, and metabolism.

The overall goals are to identify the novel hypoxia-specific therapeutic targets and ultimately to translate knowledge to breast cancer therapy.