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    Research Grants Awarded

    Role Of Adiponectin In Breast Tumor Formation And Rrogression

    Grant Mechanism:
    Postdoctoral Fellowships

    Scientific Abstract:
    Background: Breast cancer is the most common invasive cancer in women worldwide. Because there are no permanent cures for metastatic breast cancer, there is a pressing need for identifying and altering modifiable breast cancer risks. Obesity is one such modifiable risk factor. However, the mechanisms by which obesity increases the risk of breast cancer are largely unknown. Recently, the contribution of adipokines to the mechanisms by which obesity and related metabolic disorders influence breast cancer risk, has attracted extensive attention. Particularly, adiponectin and leptin have come to be recognized for their effects on breast cancer risk and tumor biology. Adiponectin, also named Acrp30, is a plasma protein produced exclusively by adipocytes. Paradoxically, obesity decreases the serum level of adiponectin. Epidemiological studies have demonstrated that serum adiponectin levels have an inverse association with breast cancer risk. One of these studies indicated that low serum adiponectin concentrations were associated with large tumors and tumors of high histological grade. In addition, a few preliminary studies also suggested that adiponectin has an anti-proliferative effect on certain breast cancer cell lines. Hypothesis: I hypothesize that adiponectin deficiency will increase the risk for mammary tumor formation in mice, and that adiponectin may directly regulate breast cancer cell proliferation, survival and migration/invasion. Specific aims: 1) Examine the role of adiponectin in mammary tumorigenesis. 2) Determine the effect of adiponectin deficiency on mammary tumor growth and metastasis in mice. 3) Investigate the role of different adiponectin isoforms, trimer, hexamer and high molecular weight, in breast cancer cell proliferation, survival and migration/invasion. Experimental design: For the first aim, I will examine whether adiponectin deficiency in mice can decrease the latency, and/or increase the incidence of breast cancer formation in mice that carry germline mutations (Brca1, Brca2 or HER-2/neu), or are exposed to carcinogens (N-methyl-N-nitrosourea (MNU) and 7,12-dimethylbenz(a)anthracene (DMBA)). For the second aim, employing mammary tumor cell implantation, I will determine whether adiponectin deficiency affects mammary tumor growth and metastasis in mice. For the third aim, I will purify different isoforms of recombinant adiponectin: trimer, hexamer and high molecular weight (HMW) complex, and examine their effects on breast cancer cell proliferation, survival and migration/invasion. Furthermore, I will investigate adiponectin signal transduction pathways in breast cancer cells. Significance: Obesity has become a worldwide threat to human health. Obesity not only leads to certain metabolic disorders, but also increases the risk for cancer formation. In addition, obesity is associated with poor prognosis of breast cancer. This proposed research will facilitate unveiling the mechanisms by which obesity increases breast cancer risk. Understanding how adiponectin regulates mammary tumor cell proliferation, survival and migration/invasion will reveal novel therapeutic targets for breast cancer.

    Lay Abstract:
    Breast cancer, the leading cause of death in American women between their late 30s and early 50s, continues to be a major health problem for women in the USA and worldwide. Financial costs of breast cancer treatment are substantial and up to $8.1 billion was used to treat breast cancer in the USA in 2004, according to the National Cancer Institute. Although the breast cancer survival rate has been improved due to screening and improved treatment, there are still no permanent cures for metastatic breast cancer. Metastasis is the spread of cancer cells from the primary tumor to other organs and is the principle reason for breast cancer related death. Thus, there is a pressing need for identifying and altering modifiable breast cancer risks, and obesity is one such modifiable risk factor. Obesity has become a worldwide threat to human health. Obesity not only leads to certain metabolic disorders, such as type 2 diabetes, but also increases the risk for cancer formation, including breast cancer. Moreover, obesity is associated with a poor outcome of breast cancer. Therefore, it is critical to clarify mechanisms by which obesity influence the risk for breast cancer formation. One possibility is that obesity affects breast cancer development and tumor growth through fat cell-specific hormones. Fat cells not only store energy but also secrete hormones that regulate multiple physiological processes. Low serum levels of adiponectin, a fat cell-specific hormone, are associated with a high risk for both breast cancer formation and larger tumor size. To this end, I propose to investigate the contribution of adiponectin to breast tumor formation and growth. I hypothesize that adiponectin deficiency will accelerate mammary tumor formation and lead to larger tumors in mice, and that adiponectin may also inhibit breast tumor cell proliferation, survival and migration/invasion. Collectively, these studies will facilitate unveiling the mechanisms by which obesity increases breast cancer risk. Furthermore, understanding how adiponectin regulates mammary tumor cell proliferation, survival and migration/invasion will reveal novel therapeutic targets for breast cancer.