β‑hCG, commonly known as the “pregnancy hormone,” may hold promise as a positive prognostic marker in the diagnosis and treatment of breast cancer. Researchers at the Rajiv Gandhi Biotechnology Centre, Kerala, have been investigating the molecular mechanisms of tumorigenesis by BRCA1 gene, the mutations of which are strongly associated with hereditary breast and ovarian cancers.
In the past years, the breast cancer suceptibility genes, BRCA 1 and BRCA 2, have gained significant attention due to their role in hereditary breast cancer. These genes are essential for DNA damage repair, and mutations in BRCA1 or BRCA2 significantly elevate the risk of developing certain cancers, particularly breast and ovarian cancers. In some cases, BRCA1 mutations lead to the development of aggressive cancer subtypes, such as triple-negative breast cancer (TNBC), which is characterised by the absence of estrogen, progesterone, and HER2 receptors. This receptor deficiency renders TNBC resistant to conventional hormone-based therapies.
Researchers from the Rajiv Gandhi Biotechnology Centre, Kerala, have uncovered a significant link between β‑hCG, a hormone commonly associated with pregnancy, and BRCA1-deficient breast cancers. This study, recently published in Heliyon, highlights β‑hCG as a potential prognostic marker and therapeutic target for aggressive breast cancer subtypes, particularly TNBC and high-grade metaplastic carcinoma.
“Our initial goal was to explore the molecular mechanisms that drive tumour development in BRCA1-deficient conditions, given the increased breast cancer risk associated with these mutations,” explained Priya Srinivas, the principal investigator of the study. As the connection between BRCA1 mutations and TNBC became clearer, the team turned their attention to other molecular markers that could influence tumour behaviour in BRCA-mutated cancers. This focus eventually led them to study β‑hCG (beta-human chorionic gonadotropin).
β‑hCG is well-known for its role in pregnancy, where it supports the early embryo development. However, its potential role in cancer remains largely unexplored. Using various gene expression platforms, the researchers analyse β‑hCG expression across different cancer types. They found that β‑hCG is markedly increased in aggressive forms of breast cancer, like TNBC and high-grade metaplastic carcinomas, both of which have poor prognosis.
This suggests that β‑hCG might play a key role in the growth and spread of BRCA1-related cancers.
The study further employed TIMER2, a tool used to measure immune cell activity in tumors, to examine BRCA1-mutated cancers. The researchers observed higher levels of immune cell infiltration in these cancers, indicating a potential interaction between β‑hCG and the immune system, which could affect the tumor’s microenvironment and influence its response to treatment.
A major breakthrough in the study was identifying the precise location where BRCA1 binds directly to the β‑hCG gene. This finding suggests that mutations in BRCA1 disrupt this interaction, leading to over-expression of β‑hCG. Neethu Krishnan, the study’s first author of the manuscript, noted that these results align with their in-vitro experiments, which confirmed that BRCA1 directly regulates β‑hCG levels.
The study found that the p53 gene, which helps prevent tumours, increases β‑hCG production in breast cancer cells while also reducing BRCA1 levels through a feedback loop. This suggests that β‑hCG could be a promising treatment target for cancers linked to BRCA1 mutations. However, the research was limited by the small amount of data on BRCA1 mutations, highlighting the need for further studies with larger datasets.
Srinivas stressed that more research is required to confirm whether targeting β‑hCG could effectively treat breast cancer.
While β‑hCG is well-known for its role in pregnancy and generally does not affect other bodily functions in non-pregnant conditions, its ability to suppress the immune system during pregnancy raises questions about its behaviour in cancer. To fully understand its potential as a treatment, further lab studies and clinical trials will be essential.
Revathy Nadhan, a postdoctoral researcher at OU Health Stephenson Cancer Center, USA, who was not involved in the current study, highlighted its potential impact, “Blocking β‑hCG, an immune suppressor over-expressed in BRCA1-defective TNBCs, presents a promising therapeutic approach with broad clinical applications”.
Srinivas opined that ”Strategies like passive immunisation with β‑hCG antibodies or antibody-drug conjugates could offer innovative and effective treatments, providing valuable leads for future clinical trials targeting these aggressive cancers”.