An estrogen receptor that promotes cancer also causes drug resistance


Date:
September 23, 2021
Source:
University of California - San Francisco
Summary:
Cancer cells proliferate despite a myriad of stresses -- from
oxygen deprivation to chemotherapy -- that would kill any ordinary
cell. Now, researchers have gained insight into how they may be
doing this through the downstream activity of a powerful estrogen
receptor. The discovery offers clues to overcoming resistance to
therapies like tamoxifen that are used in many types of breast
cancer.



FULL STORY ========================================================================== Cancer cells proliferate despite a myriad of stresses -- from oxygen deprivation to chemotherapy -- that would kill any ordinary cell. Now, researchers at UC San Francisco have gained insight into how they may
be doing this through the downstream activity of a powerful estrogen
receptor. The discovery offers clues to overcoming resistance to therapies
like tamoxifen that are used in many types of breast cancer.


========================================================================== Estrogen receptor a (ERa) drives more than 70 percent of breast
cancers. The new research published Sept. 23, 2021, in Cell discovered
that in addition to its well-known activity in the nucleus, it can also
help malignant cells overcome innate anti-cancer mechanisms and develop resistance to treatment.

In the nucleus, ERa regulates the conversion of DNA to messenger RNA
(mRNA), a process known as transcription. Once formed, the mRNA strand
travels from the nucleus into the cytoplasm, where it instructs ribosomes
to make protein, a process known as translation. To their surprise,
the researchers found that ERa plays a role in this process as well by
binding to the newly formed mRNA.

"The RNA-centric function of the estrogen receptor has so far been hidden behind its well-established role as a transcription factor, and may have
been supporting cancer progression on the sly," said Yichen Xu, PhD, a postdoctoral fellow in urology at UCSF and the first author of the study.

A New Role for ER? Using breast cancer cell lines, the research team
saw how ERa tends to bind to RNAs, particularly messenger RNAs (mRNAs)
involved in cancer progression. Some of these mRNAs keep cells from
committing suicide when they accumulate too many harmful mutations. Others
help them proliferate under extremely difficult conditions, such as
lack of oxygen or nutrients. Still others help them evade therapeutic interventions.



========================================================================== "Cancer cells are constantly being exposed to stress, and these cells
have learned to live with it," said Davide Ruggero, PhD, the senior
author of the study, a professor of urology and the Helen Diller
Family Endowed Chair in Basic Research at UCSF. "Many compounds used to
kill cancer induce stress in the cancer, and most of the cancer cells
die. But some eventually find a way to bypass the stress induced by
the therapy." Implications for Cancer Therapy Endocrine therapies,
such as tamoxifen, block the transcription activity of ERa in a cancer
cell's nucleus. Although they can be highly effective at first for most patients with ERa-positive breast cancer, a significant number develop
drug resistance.

To understand ERa's role in this, Ruggero's team analyzed cancer cells
from 14 patients diagnosed with ERa-positive breast cancer and found
they had elevated levels of ERa mRNA targets.

Then they experimented with breast cancer cell lines that had acquired resistance to tamoxifen, both in tissue culture and in mouse xenografts.

Inhibiting the ERa RNA-binding activity restored tamoxifen's potency
against the tumors in mice. It also made the cells in culture more
sensitive to stress and apoptosis.

A better understanding of ERa's many functions could help optimize
current treatments -- like tamoxifen -- as well as lead to new therapeutic targets.

Compounds that target translational control in cancer are already in
the clinic and can now be tested for potency against breast cancers that
are associated with ERa expression.

Much more work needs to be done, however, to really understand how ERa
controls RNA biology in the cytoplasm. And other regulators of RNA could
yet be discovered.

"One of the reasons why we haven't cured cancer is because we still
don't fully understand how it works," Ruggero said. "If we start from
the most basic point of view, we might be able to discover new things." ========================================================================== Story Source: Materials provided by
University_of_California_-_San_Francisco. Original written by Laura
Kurtzman. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Yichen Xu, Peiwei Huangyang, Ying Wang, Lingru Xue, Emily Devericks,
Hao
G. Nguyen, Xiuyan Yu, Juan A. Oses-Prieto, Alma L. Burlingame,
Sohit Miglani, Hani Goodarzi, Davide Ruggero. ERa is an RNA-binding
protein sustaining tumor cell survival and drug resistance. Cell,
2021; DOI: 10.1016/j.cell.2021.08.036 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/09/210923122418.htm

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