Unfortunately, many molecules which drive cancer development and growth are considered “undruggable.” In short, this means that drugs are unable to bind to or address these molecules due to size, shape, or location. According to Medical XPress, researchers from the University of California San Diego School of Medicine are now working on overcoming this burden in patients with hard-to-treat breast cancer, such as triple-negative breast cancer. In doing this, the researchers are focusing on RNA-binding proteins, which can play a role in gene expression and cellular control. While RNA-binding proteins can be protective, they can also spur tumor growth and development. Thus, researchers believe this could be a new therapeutic target for cancer. Check out the full study findings published in Molecular Cell.
In an unrelated 2021 article published in Genetics and Molecular Biology, the authors describe RNA-binding proteins as:
[having] important functions in the regulation of gene expression. [RNA-binding proteins] play key roles in post-transcriptional processes…such as splicing regulation, mRNA transport and modulation of mRNA translation and decay.
Within this particular study, researchers used the concept of synthetic lethality. To begin, researchers engineered human breast cells to produce too much of a certain cancer-causing or cancer-driving molecule. Next, the researchers searched for cellular vulnerabilities. To do this, they used CRISPR to silence RNA-binding proteins (one at a time) in breast cancer cells. Next, researchers found a total of 57 RNA-binding proteins which can destroy cancerous cells without harming normal, non-cancerous cells.
After evaluating these 57 proteins, researchers determined that YTHDF2 was the best drug target. Next, the researchers used CRISPR to remove YTHDF2 from mice models of triple-negative breast cancer. To develop these models, researchers transplanted human tumors into the mice. Removing YTHDF2 showed promise. In fact, the tumor size decreased by around 10x.
Surveying Targets by APOBEC-Mediated Profiling (STAMP)
The researchers also developed Surveying Targets by APOBEC-Mediated Profiling (STAMP), a technique allowing researchers to understand how RNA molecules and RNA-binding proteins are interrelated. Through STAMP, researchers were able to understand how breast cancer cells act with (and without) YTHDF2. Findings included:
- Breast cancer cells without enough YTHDF2 died through cellular apoptosis. Overall, this helps prevent or inhibit tumor formation.
- Mice models lacking YTHDF2 had no tumors and were relatively healthy. As a result, researchers believe that YTHDF2 inhibitors would be safe as a potential treatment option.
While there is no definitive cause for breast cancer, medical professionals understand that abnormal (cancerous) cells begin to proliferate in breast tissue. However, an estimated 10% of breast cancer diagnoses stem from BRCA1 or BRCA2 gene mutations. For example, up to 45% of females with BRCA2 mutations develop breast cancer before 70 years old. While breast cancer is the 2nd most common female cancer, it may also affect males. Other risk factors include obesity, radiation exposure, alcohol use, menstruating early or going through menopause late, or never having been pregnant.
As described above, another form of breast cancer is triple-negative. BreastCancer.org describes triple-negative breast cancer as:
cancer that tests negative for estrogen receptors, progesterone receptors, and excess HER2 protein. These results mean the growth of the cancer is not fueled by the hormones estrogen and progesterone, or by the HER2 protein, [and] does not respond to hormonal therapy medicines or medicines that target HER2 protein receptors.
Unlike other forms of breast cancer, triple-negative breast cancer is often aggressive, associated with poorer prognoses, and higher-grade.
Symptoms of breast cancer include:
- A lump in breast tissue
- Inverted nipples
- Breast skin irritation or dimpling
- Abnormal nipple discharge
- Change in breast size, shape, or appearance
- Breast skin pitting, peeling, scaling, crusting, redness, or flakiness
- Swollen lymph nodes
- Nipple pain
Learn more about breast cancer.