ABSTRACT
Obesity is a strong risk factor for breast cancer in post-menopausal females and an adverse prognostic indicator in both pre-and post-menopausal females. Leptin, the product of the obesity (Ob) gene and it’s interaction with its receptor (Ob-R) has been shown to impact the development of breast cancer in murine models (Gillespie et al., 2012). The interaction between leptin and VEGF/VEGF receptor in promoting angiogenesis has also been documented (Guo and Gonzalez-Perez 2011). Leptin is a pro-proliferative, pro-inflammatory and pro-angiogenic factor. A complex crosstalk between leptin and the pro-inflammatory cytokine, IL-1, and the embryogenic/angiogenic signal, Notch, has been reported in breast cancer (Guo and Gonzalez-Perez 2011). Leptin is a 167-amino acid protein produced by the leptin gene (LEP). The LEP gene has been localized in humans to the 7q31.3 chromosome. It consists of three exons separated by two introns (Isse et al. 1995). Leptin is important in the regulation of adipose-tissue mass and body weight by regulating food intake and energy expenditure. Leptin is produced by the adipocytes of white adipose tissue. Its effects are mediated through binding to a specific receptor, encoded by LEPR located on human chromosome 1p31 (Paracchini et al. 2005). The leptin receptor, LEPR (Ob-R), has six isoforms produced by alternative RNA splicing of the ob gene. Based on these structural differences the receptor isoforms are classified as either long, short or soluble. The full length isoform (Ob-Rb) is the only isoform able to fully transduce activation signals into the recipient cell. The four short isoforms, Ob-Ra, Ob-Rc, Ob-Rd and Ob-Re are able to bind Janus kinases (JAKs). The soluble short isoform,
Ob-Re, can regulate serum leptin concentration, serve as a carrier protein, and transduce signals to recipient cells (Gorska et al. 2010). Isoforms of the leptin receptor have been identified in many tissues including the mammary gland, male and female reproductive organs, the gut, lung and hypothalamus. Several polymorphisms in the LEP gene as well as the LEPR gene have been identified. Paracchini et al. (Paracchini et al. 2005) recognized the ethnic variation in allelic frequencies of the polymorphisms LEP A19G, LEPR Q223R, K109R, and K656N. However, no evidence of an association between these genes and obesity was found through metaanalysis of available data (Paracchini et al. 2005). This conclusion was also supported by Heo et al. who previously analyzed the association and linkage of LEPR polymorphisms LEPR Q223R, K109R, and K656N to body mass index and waist circumference (Heo et al. 2002). It must be acknowledged that there is an increased incidence of obesity among certain ethnic groups. Data from the National Health and Nutrition Examination Survey (NHANES) 2007-2008 reported obesity prevalence rates of 33% among Non-Hispanic white women ages 20 and above (64). Non-Hispanic black women had prevalence rates of 49.6% and Hispanics, including Mexican Americans had prevalence rates of 43%. Obesity was defined as having a body mass index (BMI) ≥ 30 (Flegal et al. 2010). It must also be acknowledged that obesity is a multifactorial phenomenon and positing a direct link between obesity and breast cancer pathogenesis is problematic. Increasing BMI is positively correlated with increased risk of death from cancer in general (Calle et al. 2003). Obese patients fare worse than lean patients in terms of recurrence rates and prognosis. Increasing BMI was been shown to be associated with increased death rates for breast cancer. Ewertz et al documented a 38% increase in the risk of breast cancer death over 30 years in patients with a BMI ≥ 30 kg/m2 (Ewertz et al. 2011). Nonetheless, as leptin, the product of the obesity gene, is central in regulating food intake, it can be postulated that a change in its expression as brought about by a gene polymorphism may possibly impact on all the known functions mediated by leptin/Ob-R binding. Indeed, Avery et al performed a retrospective case-case study of 164 African-American and 172 White breast cancer patients (Avery 2011). Mean serum levels of leptin were higher in the African-American patients as compared to the White patients after adjusting for BMI. There was also a trend toward higher leptin levels in patients with triple negative tumors (p=0.06). Additionally, Cohen et al (Cohen et al. 2012) performed a cross-sectional study of 915 white and 892 black women enrolled in the Southern Community Cohort Study. Their findings revealed that leptin levels differ between races even after adjusting BMI. Blacks had higher leptin levels when compared to whites (mean 22.4 vs 19.0 ng/ml; p< 0.0001 unadjusted and 22.7 vs 18.8 ng/ml adjusted (Cohen et al. 2012). It has been mentioned previously in this chapter that African-American patients tend to have a higher incidence of triple negative breast cancers as compared to non-African-American patients (Carey et al. 2006).
