• Fat-secreted molecule lowers response to

    From ScienceDaily@1:317/3 to All on Tue Nov 9 21:30:36 2021
    Fat-secreted molecule lowers response to common cancer treatment

    Date:
    November 9, 2021
    Source:
    Johns Hopkins Medicine
    Summary:
    Leptin, a molecule produced by fat cells, appears to cancel out the
    effects of the estrogen-blocking therapy tamoxifen, a drug commonly
    used to treat and prevent breast cancers, suggests a new study.



    FULL STORY ========================================================================== Leptin, a molecule produced by fat cells, appears to cancel out the
    effects of the estrogen-blocking therapy tamoxifen, a drug commonly
    used to treat and prevent breast cancers, suggests a new study led by researchers from the Johns Hopkins Kimmel Cancer Center. The findings, published online Aug. 13 in npj Breast Cancer, could help explain why
    obese patients with breast cancer often experience worse outcomes,
    and may eventually lead to more effective treatments for this group.


    ========================================================================== "Obese women may not get the full benefit of tamoxifen, one of the
    most widely prescribed medications for estrogen receptor-positive
    breast cancer treatment and prevention," says study leader Dipali
    Sharma, Ph.D., professor of oncology at the Johns Hopkins University
    School of Medicine. "With obesity increasing worldwide and 40% of the
    U.S. population already obese, there are a lot of breast cancer patients
    at risk for poor outcomes." Estrogen receptor-positive breast cancer
    is the most common type of breast cancer, and relies on the hormone
    estrogen to grow and spread. As a result, it usually responds well to
    hormone therapies that interfere with the body's production of estrogen.

    Researchers have long known that obesity is associated with an
    increased risk of breast cancer, as well as larger tumors, more
    metastatic progression, a higher risk of recurrence and worse overall
    survival. However, Sharma says, the reasons for these connections have
    been unclear.

    She and her colleagues suspected that some of these poor outcomes may
    be due to a worse response to cancer therapies, an effect influenced by endocrine molecules -- cytokines -- produced by fat cells. They focused
    on leptin in particular, a fat-secreted hormone that plays a role in
    producing feelings of satiety and has been linked to cancer growth
    and progression.

    To see whether leptin might affect therapeutic response, the researchers
    fed mice a high-fat diet for eight weeks, causing these animals to become
    obese - - which increased the animals' circulating leptin levels. They
    then implanted human estrogen receptor-positive breast cancer cells,
    a type responsible for nearly 70% of breast cancer cases, in the mammary
    pads of the obese mice and in lean animals.

    When Sharma and her team gave these mice tamoxifen, the lean animals'
    tumors responded well, regressing quickly. But the obese animals' tumors
    didn't shrink; rather, they responded as if they hadn't been treated
    at all.

    Administering leptin along with tamoxifen caused the same poor response
    in lean animals, suggesting that leptin was somehow negating tamoxifen's cancer- fighting effects.

    Searching for a mechanism for this phenomenon, Sharma and her colleagues
    found that leptin appears to activate the estrogen receptors on breast
    cancer cells, even when estrogen isn't present, in turn setting off
    a cascade of cancer- promoting genes. One key gene in this cascade is
    Med1, which associates with dozens of obesity-related genes. When the researchers silenced this gene, rendering it nonfunctioning, implanted
    tumors responded to tamoxifen even in the presence of leptin. The
    researchers were able to achieve this same effect by giving mice another fat-secreted molecule called adiponectin or a compound called honokiol
    that's derived from magnolia trees. Both agents target Med1 and were
    previously known to have a protective effect on cancers.

    Sharma says interventions that can lower leptin, such as losing weight,
    or target Med1, such as adiponectin or honokiol, could eventually be used
    to improve tamoxifen's success in obese patients with breast cancer. She
    and her team are studying some of these potential treatments in mice,
    a step toward testing them in human clinical trials.

    This work was supported by grants from the National Cancer Institute
    of the National Institutes of Health (RO1CA204555), the Avon Foundation
    and the Breast Cancer Research Foundation (90047965).

    ========================================================================== Story Source: Materials provided by Johns_Hopkins_Medicine. Note:
    Content may be edited for style and length.


    ========================================================================== Journal Reference:
    1. Arumugam Nagalingam, Sumit Siddharth, Sheetal Parida, Nethaji
    Muniraj,
    Dimiter Avtanski, Panjamurthy Kuppusamy, Justin Elsey, Jack
    L. Arbiser, Bala'zs Győrffy, Dipali Sharma. Hyperleptinemia in
    obese state renders luminal breast cancers refractory to tamoxifen
    by coordinating a crosstalk between Med1, miR205 and ErbB. npj
    Breast Cancer, 2021; 7 (1) DOI: 10.1038/s41523-021-00314-9 ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2021/11/211109095351.htm

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