The American Cancer Society's 2014 report revealed that incidence rates are decreasing or stable for most cancers in the United States since 1999. Some notable exceptions are liver cancer in African Americans and Hispanics, endometrial cancer in African American women, colorectal cancer in patients under 50, and pancreatic cancer in every demographic.
In the tissues originating all these tumors, the nuclear receptors SF-1 and LRH-1 mediate genetic programs that are essential determinants of development, differentiation and adult physiology. Despite this importance, little is known about how these transcription factors are turned on and off.
At the molecular level, these proteins bind phosphoinositides (PIPs), small signaling lipids essential in PTEN-dependent cancers. We recently uncovered a novel mechanism that these lipids and their signaling enzymes use to regulate SF-1 and LRH-1 gene expression. This mechanism now links dysregulation of these pathways to the cancers mentioned above.
Our central hypothesis is that lipids bound to nuclear proteins are directly remodeled by lipid signaling enzymes, namely the PI3-kinase inositol polyphosphate multikinase (IPMK) and the PTEN lipid phosphatase. This hypothesis is a clear departure from the standard dogma that PI3-kinases and PTEN only act on phosphoinositides within cellular membrane systems.