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

--- up 9 weeks, 5 days, 9 hours, 25 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)