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Drug resistance by Cancer promoting Estrogen Receptor

Cancer cells thrive despite a variety of stressors that would kill any other cell, such as oxygen deprivation and chemotherapy. Researchers at UC San Francisco have now discovered how they may be accomplishing this by exploiting the downstream activation of a strong estrogen receptor. The discovery may point to a way to overcome resistance to drugs like tamoxifen, which are used to treat a variety of breast cancers.

More than 70% of breast cancers are caused by the estrogen receptor (ER). According to new research published in Cell on September 23, 2021, it can enable malignant cells bypass intrinsic anti-cancer mechanisms and establish treatment resistance in addition to its well-known function in the nucleus.

ER controls the conversion of DNA to messenger RNA (mRNA) in the nucleus, a process known as transcription. The mRNA strand is generated in the nucleus and then travels to the cytoplasm, where it guides ribosomes to build protein, a process known as translation. Surprisingly, the researchers discovered that ER is involved in this process as well, by binding to freshly produced mRNA.

"The estrogen receptor's RNA-centric activity has been buried so far behind its well-established role as a transcription factor, and may have been secretly encouraging cancer growth," said Yichen Xu, PhD, a postdoctoral fellow in urology at UCSF and the study's first author.

The researchers looked at how ER binds to RNAs, particularly those important in cancer growth, using breast cancer cell lines. When cells acquire too many damaging mutations, some of these mRNAs prevent them from committing suicide. Others aid their proliferation in the face of adversity, such as a shortage of oxygen or nutrition. Others assist them in avoiding therapeutic interventions.

"Cancer cells are continually exposed to stress, and these cells have learnt to live with it," said Davide Ruggero, PhD, a professor of urology and the Helen Diller Family Endowed Chair in Basic Research at UCSF, who is also the study's senior author. "Many cancer-killing substances cause cancer cells to become stressed, and the majority of cancer cells die as a result. However, some people finally figure out a means to avoid the therapy's stress."

Tamoxifen and other endocrine treatments limit the transcription activity of ER in the nucleus of cancer cells. Although most patients with ER-positive breast cancer benefit from them at first, a considerable number develop treatment resistance.

To figure out how ER plays a part in this, Ruggero's team looked at cancer cells from 14 patients with ER-positive breast cancer and discovered that they had higher levels of ER mRNA targets.

The researchers then used tissue culture and mice xenografts to test breast cancer cell lines that had developed resistance to tamoxifen. Tamoxifen's effectiveness against cancers in mice was restored when the ER RNA-binding activity was inhibited. It also increased the sensitivity of the cells in culture to stress and apoptosis.

A deeper knowledge of ER's numerous activities could aid in the optimization of current medicines, such as tamoxifen, as well as the identification of new therapeutic targets. Compounds that target cancer translational control are currently in clinical trials, and they may now be assessed for potency against breast tumors linked to ER expression.

However, much more research is needed to fully comprehend how ER regulates RNA biology in the cytoplasm. Other RNA regulators could be identified in the future.

"We still don't fully understand how cancer operates, which is one of the reasons we haven't cured it," Ruggero added. "We might be able to find new things if we start from the most fundamental point of view."

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