Lipid Regulatory Proteins as Potential Therapeutic Targets for Ovarian Cancer in Obese Women

SIMPLE SUMMARY: Obesity is a recognized epidemic worldwide. Ovarian cancer (OvCa), the most lethal gynecologic malignancy, is characterized by widely disseminated metastatic implants in the peritoneal cavity. Metastatic lesions infiltrate the omentum, as well as perigonadal adipose and other visceral adipose depots. Meta-analyses support a link between obesity and OvCa progression, metastasis and survival. Recent studies demonstrated a crucial role of lipid regulatory proteins in OvCa growth and metastasis. The aim of this review is to summarize current understanding of the relationship between lipid regulatory proteins, obesity and OvCa progression, as well as the potential therapeutic targets for antitumor therapy in obese OvCa patients, with an emphasis on the role of sterol regulatory element binding protein 1 (SREBP1). ABSTRACT: Obesity has become a recognized global epidemic that is associated with numerous comorbidities including type II diabetes, cardiovascular disease, hypertension, and cancer incidence and progression. Ovarian cancer (OvCa) has a unique mechanism of intra-peritoneal metastasis, already present in 80% of women at the time of diagnosis, making it the fifth leading cause of death from gynecological malignancy. Meta-analyses showed that obesity increases the risk of OvCa progression, leads to enhanced overall and organ-specific tumor burden, and adversely effects survival of women with OvCa. Recent data discovered that tumors grown in mice fed on a western diet (40% fat) have elevated lipid levels and a highly increased expression level of sterol regulatory element binding protein 1 (SREBP1). SREBP1 is a master transcription factor that regulates de novo lipogenesis and lipid homeostasis, and induces lipogenic reprogramming of tumor cells. Elevated SREBP1 levels are linked to cancer cell proliferation and metastasis. This review will summarize recent findings to provide a current understanding of lipid regulatory proteins in the ovarian tumor microenvironment with emphasis on SREBP1 expression in the obese host, the role of SREBP1 in cancer progression and metastasis, and potential therapeutic targeting of SREBPs and SREBP-pathway genes in treating cancers, particularly in the context of host obesity.