Basic Science Newsbrief August 2011

 

August 2011

 

"Leptin signaling and breast cancer in obese, post-menopausal women"

by Gerald V. Denis

 

Weight gain among survivors of diverse types of cancers is common and is associated with poor prognosis. In addition, obese and overweight populations exhibit greater morbidity rates and reduced survival from breast cancer and other cancers for which obesity is a risk factor. For example, about twenty years’ worth of epidemiological evidence has identified an elevated risk of luminal breast cancer associated with obesity in post-menopausal women. In the US, obesity is estimated to contribute significantly to 11,000 – 18,000 excess breast cancer deaths. Intense study of the molecular and cellular mechanisms that account for this phenomenon has revealed critical roles for elevated leptin and insulin, and reduced adiponectin, in the at-risk population.

 

Specifically, leptin-resistant, obese individuals show elevated incidence of both colorectal cancer and breast cancer; evidence from in vitro model systems suggests that leptin directly promotes proliferation through Jak2/Stat3 signal transduction initiated at the leptin receptor in both colorectal and breast tissues. Furthermore, obese, metabolically unhealthy individuals exhibit lower serum levels of adiponectin, an insulin-sensitizing adipokine that has also been linked to anti-proliferative, anti-cancer properties, although the relevant mechanisms have been less intensively studied. The Cleary group at the University of Minnesota have proposed that adiponectin and leptin define a metabolic axis which, when thrown off balance, is carcinogenic or releases constraints on pre-malignant or early-malignant states. The relevant molecular mechanisms here are insufficiently understood, but may relate to the likely link between obesity-associated inflammation and carcinogenesis. In addition to leptin, the cytokines typically elevated in the chronic inflammatory state of metabolically unhealthy adipose tissue, such as interleukin-1β, -6, -8, C-reactive protein and tumor necrosis factor (TNF)-α, also appear to be key players in carcinogenesis. Crosstalk among breast secretory cells, infiltrating inflammatory cells or serum cytokines, and adipocytes are clearly relevant to breast carcinogenesis. The metabolic and inflammatory characteristics of fat acquire paramount importance in obesity when it is appreciated that, in both humans and mice, breast luminal and basal cells are essentially residents of a large fat pad.

 

The Berger group at Case Western have just reported an interesting test of the functional relationships in a well established, mouse model system for breast cancer (Endocr Relat Cancer 18: 491–503; 08/01/2011). This mouse genetic model for breast cancer that uses proto-oncogene expression from mammary tumor virus creates basal-like tumors, which models carcinogenesis of the dangerous, ‘triple negative’ (estrogen receptor-, progesterone receptor- and HER2/neu-negative) cancers of basal cell origin in humans. When transplanted into obese leptin receptor-deficient (db/db) mice, tumors grew dramatically, but not when transplanted into obese leptin-deficient (ob/ob) mice. The parallel design emphasizes the importance of leptin in triple-negative breast carcinogenesis, although interpretation in this model is somewhat complicated by abnormalities in T-cell function, possibly including T-cell tumor surveillance. The report has important translational significance and suggests that in obese clinical populations, evaluation of leptin resistance (currently not clinically established, but potentially measured by elevated leptin and low adiponectin) should be included in assessment of cancer risk and intervention. Conclusions from the model cannot be drawn at this stage regarding crosstalk with inflammatory pathways or with estrogen receptor signaling in luminal breast cancer. It also remains to be determined whether women with elevated leptin but also less severe depletion of serum adiponectin, who may be members of the so-called ‘metabolically healthy obese’ cohort, have an attenuated risk of breast cancer, because adiponectin may oppose the carcinogenic action of elevated leptin. More detailed clinical studies of well matched subjects are obviously in order and will help stratify at-risk patients.

 

Interested in highlighting your research in the TOS Basic Science Newsbrief? Send ideas to the Editors, Dr. Gerald V. Denis ( This e-mail address is being protected from spambots. You need JavaScript enabled to view it ) or Dr. Barbara Nikolajczyk ( This e-mail address is being protected from spambots. You need JavaScript enabled to view it ), for consideration.

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