Scientists Identify Potential MicroRNA Target for Overcoming Breast Cancer Resistance

Estrogen receptor-α coactivator MED1 is overexpressed in 40%-60% of human breast cancers, and its high expression is directly associated with lower disease-free survival in patients receiving anti-estrogen therapy. However, the molecular mechanism of MED1 upregulation and activation in resistance to breast cancer therapy is still unclear to researchers.

Recently, in a research report entitled "miR-205 Regulates Tamoxifen Resistance by Targeting Estrogen Receptor Coactivator MED1 in Human Breast Cancer" published in the international journal Cancers, scientists from the University of Cincinnati College of Medicine and other institutions identified a special microRNA chain through research that may serve as a potential new target to overcome breast cancer therapy resistance and improve patient treatment outcomes.

Researcher Dr. Xiaoting Zhang said that about 75% of breast cancer patients will use anti-estrogen therapy, but only about half of them will have a recurrence of the disease at some point and develop a certain degree of resistance to the therapy. Previously, we identified a special protein called MED1 that is produced at high levels in 40%-60% of breast cancers. MED1 plays a key role in mediating therapy resistance in estrogen receptors (ERs) and the protein HER2, but researchers did not know how it was produced at such high levels and caused resistance to therapy.

Based on this study, researchers tried to understand why MED1 expression was so high in these therapy-resistant breast cancers. The researchers focused on microRNAs, which are small strands of non-coding genetic material in cells that can regulate the expression of different genes. The 2024 Nobel Prize in Physiology or Medicine was awarded to scientists who discovered microRNAs. These non-coding RNAs, including microRNAs, are where researchers are heading. Non-coding regions make up about 90% of the human genome (which used to be thought to be junk). But now people are beginning to realize that the transcription of these non-coding RNAs actually plays a vital role, such as regulating the expression and function of proteins.

Figure 1. miR-205 expression inversely correlates with MED1 in tamoxifen-resistant breast cancer. (Ouyang B, et al., 2024)

In this study, the researchers found that a strand of microRNA called miR-205 may have a specific sequence that regulates the production of MED1. They then further analyzed a human breast cancer database to confirm that there may be a negative correlation between miR-205 and MED1 levels. So if MED1 levels are high, miR-205 levels are actually reduced. Essentially, this microRNA blocks the production of MED1. The researchers then found that it was actually associated with patient outcomes. So if miR-205 levels are low in the body, then MED1 levels are high. And the cancer actually becomes somewhat resistant to therapy, and patients have poorer outcomes.

The researchers also found that in addition to MED1, miR-205 can also regulate the protein HER3. As part of the four-member HER protein family, HER3 is known to play a key role in the process of resistance to therapy along with HER2. Specifically, the researchers found that HER3 regulates the activation of the MED1 protein. But not only do we have more MED1, we also have more active MED1. So it's like a dual regulation, that is, miR-205 can regulate both MED1 and HER3. Subsequent studies using in vitro human breast cancer cell lines and in vivo animal models further confirmed the findings and their functional significance.

Although more research is needed, Zhang said that by blocking the production and activity of MED1, enhancing the level of miR-205 may be a different potential effective means to overcome breast cancer resistant to therapy. In summary, the results of this study suggest that miR-205 may act as a negative regulator of MED1 and HER3, thereby affecting the regulatory mechanism of the HER3-PI3K/Akt-MED1 axis in the process of anti-estrogen resistance, and may serve as a potential therapeutic solution to overcome resistance to therapy.