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Fat tissue-derived hormone leptin increases e-cadherin expression, obesity-breast cancer link noted

Federation of American Societies for Experimental Biology

Being obese increases the risk of breast cancer in post-menopausal women, shortens the time between return of the disease and lowers overall survival rates. Italian researchers speaking at Experimental Biology 2007 in Washington, DC, now report evidence on how leptin, a hormone found in fat cells, significantly influences breast cancer development and progression in mice. This new understanding, says Dr. Sebastiano Ando, establishes a new mechanism for the link between obesity and breast cancer and suggests new targets for drugs that could intervene in that mechanism.

Dr. Ando's presentation on Sunday, April 29 is part of the scientific program of the American Society of Investigative Pathology.

Leptin, an adipocyte-derived hormone, is best known for its efforts to send messages to the body that no more food is needed, a process that may go awry in many people with obesity. But it also is involved in many other processes, from reproduction and lactation to cell differentiation and proliferation. Leptin is activated by signals from the leptin receptor ObR, and it is this partnership that has previously been found to be involved in the development of breast cancer. It was recently reported, for example, that leptin was detected in 86.4 percent of primary breast tumors and that its expression was highly correlated with ObR.

In previous studies in Dr. Ando's laboratory, leptin was demonstrated to play a significant role in promoting breast cancer in obese women by increasing the amount of estrogen (estradiol) in breast tissue. In the current study, the researchers found that leptin also upregulated or increases the production of E-cadherin, an intercellular adhesion molecule generally viewed as a tumor suppressor. The researchers grafted human breast cancer tissue in "nude" mice (genetically bred to be unable to reject tumors and therefore a frequently used animal in cancer research) and also in a three dimensional tissue culture which closely mimics biological features of tumors. The results were the same in both. Combined exposure to leptin and estradiol increased tumor size, sometimes doubling it, and these changes correlated with an increase in E-cadherin.

Dr. Ando and his colleagues believe from their data that it is reasonable to suggest that the tumor suppressor E-cadherin may serve as a tumor enhancer when exposed to leptin and estradiol, that its ability to help cells aggregate then enhances the transformation of normal cells to cancerous cones, stimulating the growth of tumor mass.

When the researchers used an E-cadherin antibody or a calcium-chelating agent to block E-cadherin function in the present of estradiol, this enhanced cell growth stopped.

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This work is part of an on-going research project concerning inhibition of the effects of leptin and estradiol on breast cancer. It was supported in part by an award from the Associazione Italiana per la Ricerca sul Cancro (AIRC).

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