Molecular networks could explain racial disparity in triple negative
breast cancer deaths
Study suggests new combination approach for treating aggressive subset of breast cancer more common in African American women

Date:
March 15, 2022
Source:
Johns Hopkins Medicine
Summary:
Different activity in two molecular networks could help explain
why triple negative breast cancers tend to be more aggressive
in African American (AA) women compared with white American (WA)
women, a new study suggests.



FULL STORY ========================================================================== Different activity in two molecular networks could help explain why triple negative breast cancers tend to be more aggressive in African American
(AA) women compared with white American (WA) women, a new study led by
Johns Hopkins Kimmel Cancer Center researchers suggests.


==========================================================================
The findings, published online Dec. 20 in eLife, may explain the marked
racial disparity in mortality for this subset of breast cancer and offer
new strategies for treating this deadly disease.

"The incidence of breast cancer in African American women is lower than
in white American women, but mortality is higher. Our work shows the
molecular mechanisms that cause cancer cells to grow and spread faster
in African American women," says study leader Dipali Sharma, Ph.D.,
professor of oncology at the Johns Hopkins University School of Medicine
and John Fetting Fund for Breast Cancer Prevention researcher.

Better diagnosis and treatment have decreased breast cancer mortality in
the past few decades, cutting death rates by about 40%, but AA women are
still 42% more likely to die from this disease than WA women. Although AA
women have a lower incidence of breast cancer than WA women overall, the disparity in mortality can be partially explained by a higher incidence
among AA women of triple negative breast cancer, an aggressive breast
cancer subset characterized by a lack of estrogen, progesterone and HER2 receptors. However, even among triple negative breast cancers, those
in AA women tend to be even more aggressive than those in WA women, significantly decreasing AA survival rates.

To better understand this phenomenon, Sharma and her colleagues compared
the behavior of triple negative breast cancer cell lines isolated from
AA and WA women. When grown in petri dishes, the cells from AA women
multiplied at a faster pace, were more invasive to surrounding tissue,
were more likely to migrate, and had more "stem-like" cells capable of
creating new tumors compared with the cells from WA women. When placed
into mice, the cells from AA women created larger tumors faster and metastasized quicker compared with the cells from WA women.

"The triple negative breast cancer cells from African American women were
more aggressive from the get-go," says Sumit Siddharth, first author on
the paper and postdoctoral fellow at Johns Hopkins Medicine.

Searching for the molecular mechanisms behind these differences, the researchers assessed gene activity in each of the cell lines and in tumor samples from AA and WA women. They found that two genes, known as GLI1
and Notch1, were more active in cells isolated from AA women compared
with those isolated from WA women. Both genes produce proteins known as transcription factors, explains Sheetal Parida, a study co-author and postdoctoral fellow, and are responsible for regulating large networks
of other genes that can broadly affect cell function.

To determine whether GLI1 and Notch1 could serve as effective targets
for triple negative breast cancers, the researchers dosed the cell lines
from WA and AA women with an inhibitor for each of these two genes along
with a common chemotherapy agent used to treat these cancers. Although
each agent was largely ineffective on its own, combining all three drugs significantly inhibited growth, invasion and migration in the AA cell
lines. Treating mice with tumors grown from these cell lines had similar positive effects, reducing tumor size and metastasis.

Sharma says that she and her team plan to continue to test GLI1 and
Notch1 inhibitors in mouse models of triple negative breast cancers to
find the best combination with chemotherapies and eventually investigate
this strategy in clinical trials of patients with this disease subtype.

"Eventually," she says, "we may be able to close the survival gap
between African American and white American women with triple negative
breast cancers." In addition to Sharma, Siddharth and Parida, other researchers who contributed to this study were Nethaji Muniraj, Arumugam Nagalingam, David Lim, and Chenguang Wang from Johns Hopkins; Shawn
Hercules and Juliet Daniel from MacMaster University, Hamilton, Canada;
and Balazs Gyorffy from MTA TTK Momentum Cancer Biomarker Research Group, Budapest, Hungary.

This research was funded by the National Cancer Institute (R01CA204555).


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


========================================================================== Journal Reference:
1. Sumit Siddharth, Sheetal Parida, Nethaji Muniraj, Shawn Hercules,
David
Lim, Arumugam Nagalingam, Chenguang Wang, Balazs Gyorffy, Juliet M
Daniel, Dipali Sharma. Concomitant activation of GLI1 and Notch1
contributes to racial disparity of human triple negative breast
cancer progression. eLife, 2021; 10 DOI: 10.7554/eLife.70729 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220315141809.htm

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