Enzymes’ Role in Development, Treatment of Estrogen Receptor-positive Cancer Identified

Enzymes’ Role in Development, Treatment of Estrogen Receptor-positive Cancer Identified

Researchers have identified two new factors that may help to determine whether a patient with estrogen receptor-positive breast cancer will respond to treatment.

In addition to preventing the estrogen receptor from being degraded — and impairing drugs that target it from combating the cancer — a lack of the enzymes LATS1 and LATS2 makes cancer development much more likely, according to  “The Hippo kinases LATS1 and 2 control human breast cell fate via crosstalk with ERα.” The study was published in the journal Nature.

Researchers were studying molecular changes that contribute to the development of breast cancer when they discovered the importance of LATS1 and LATS2. The two are part of a molecular signaling route that researchers call Hippo.

When the enzymes are missing, the number of so-called luminal precursor cells in the epithelial tissue of breast glands increases. Researchers know that those cells develop into most types of human breast cancer.

“LATS balances cell fate in the breast tissue. In its absence, the equilibrium shifts and more cells that can give rise to tumors develop,” Mohamed Bentires-Alj, a professor from the Department of Biomedicine at the University of Basel, said in a news release.

The team found that LATS normally is involved in the estrogen receptor alpha being targeted for degradation in the proteasome (a protein degradation “machine” within the cell). Without LATS, estrogen receptors are not degraded.

Up to 70 percent of breast cancers produce estrogen receptors and are dependent on them to thrive. Such cancers often respond well to treatment with drugs that interfere with receptor production or function. But about a third of patients do not respond to that type of treatment, or they become resistant after some time.

“We were able to show that cancer cells without LATS no longer respond to fluvestrant (brand name Faslodex), an estrogen-receptor antagonist that promotes its degradation. They were resistant,” Bentires-Alj said.

The team also discovered how LATS interacts with other factors that contribute to cancer-cell expansion.

“Thanks to our newly gained insights into the molecular processes in healthy breast tissue, we now also better understand how cells of origin of cancer expand and why certain tumors are resistant to therapy,” Bentires-Alj said.