Leptin Regulation of Cancer Stem Cells in Breast and Gynecologic Cancer

Abstract

It is well established that obesity increases the incidence and worsens the prognosis of women's cancer. For breast cancer, women with obesity exhibit more than a twofold increase in the odds of being diagnosed with cancer, with a greater risk of advanced stage at diagnosis, and ≤40% greater risk of recurrence and death than their normal-weight counterparts. These findings are similar in gynecologic cancers, where women who are obese with a body mass index (BMI) >40 kg/m2 have up to six times greater risk of developing endometrial cancer and a 9.2% increase in mortality with every 10% increase in BMI. Likewise, patients with obesity exhibit a twofold higher risk of premenopausal ovarian cancer, and patients who are obese with advanced stage ovarian cancer have shown a shorter time to recurrence and poorer overall survival. Obesity is accompanied by changes in expression of adipose factors that act on local tissues and systemically. Once obesity was recognized as a factor in cancer incidence and progression, the adipose cytokine (adipokine) leptin became the focus of intense investigation as a putative link, with nearly 3000 publications on the topic. Leptin has been shown to increase cell proliferation, inhibit apoptosis, promote angiogenesis, and increase therapeutic resistance. These characteristics are associated with a subset of cells in both liquid and solid tumors known as cancer stem cells (CSCs), or tumor initiating cells. We will review the literature discussing leptin's role in breast and gynecologic cancer, focusing on its role in CSCs, and consider goals for targeting future therapy in this arena to disrupt tumor initiation and progression in women's cancer.

Figure 1.

Leptin has been found to play a role in breast, cervical, endometrial, and ovarian malignancies, with upregulation of leptin and LEPR in associated tissue samples. Reprinted with permission, Cleveland Clinic Center for Medical Art & Photography © 2018. All Rights Reserved.

Figure 2.

Leptin binds to the LEPR and mediates multiple downstream pathways. The JAK/STAT pathway is mediated via homo-oligomerization of JAK2, with subsequent phosphorylation and activation of STAT transcription factors, such as CPT1B and c-myc. JAK also phosphorylates Tyr985, leading to phosphorylation of SHP2 and downstream activation of ERK and associated gene expression, including the oncogene c-fos. JAK also leads to activation of the PI3K pathway, whereby AKT is phosphorylated and mTOR is subsequently activated, leading to expression of EIF4E and CAD. JNK is another pathway activated by JAK, leading to downstream expression of genes including c-Jun (oncogene) and MMP7. Reprinted with permission, Cleveland Clinic Center for Medical Art & Photography © 2018. All Rights Reserved.