Bharti Jayshankar
December 16, 2024: Researchers at the Rajiv Gandhi Biotechnology Centre, Kerala, delving into the molecular mechanisms of tumorigenesis by BRCA1 gene, found that its mutations are strongly associated with hereditary breast and ovarian cancers.
This study, recently published in Heliyon, analyzed the gene expression of β-hCG (beta-human chorionic gonadotropin) and its clinical implications across various cancers, with a focus on Breast Invasive Carcinoma (BRCA). Mutations in BRCA1 or BRCA2 significantly elevate the risk of developing breast and ovarian cancers.
Key findings
Data from multiple gene expression platforms, including UALCAN and GENT2, revealed that triple-negative breast cancer (TNBC) subtypes and high-grade metaplastic carcinoma exhibit elevated levels of β-hCG. This trend was consistent across various cancers when BRCA1 was mutated, suggesting a potential biomarker for aggressive cancer forms.
“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. Besides the connection between BRCA1 mutations and TNBC, the team also investigated other molecular markers that could influence tumour behaviour in BRCA-mutated cancer, such as β‑hCG.
The infiltration of immune cells in breast cancer cases was identified through TIMER2 analysis, indicating that β-hCG may play a role in the tumor microenvironment. The study found that most isoforms of β-hCG (CGB) are upregulated in breast cancers regardless of hormonal status when there is a mutation in the BRCA1 gene.
Research indicates that the presence of β-hCG can enhance the expression of mutant BRCA1 protein while simultaneously reducing the levels of wild-type BRCA1 protein in cells where BRCA1 is functional, illustrating its intricate relationship with breast cancer and the potential for conflicting outcomes based on BRCA1 status.
This relationship between β-hCG and BRCA1 is underscored by the findings that β-hCG can directly bind to the BRCA1 promoter, indicating a regulatory mechanism where BRCA1 influences β-hCG expression and vice versa. Studies show that when BRCA1 function is restored, β-hCG levels decrease, highlighting a protective role for BRCA1 in regulating β-hCG, which could impact breast cancer progression.
Additionally, β-hCG is linked to increased tumor aggressiveness, promoting cell migration and invasion in BRCA1 mutant breast cancer cells through pathways like the TGFBRII signaling axis, which further complicates its classification as a mere biomarker.
It was confirmed that BRCA1 directly binds to the β-hCG promoter, which influences its expression.
Methodology
The study utilized comprehensive data from various platforms including GEPIA2, TIMER2, and LinkedOmics to analyze gene expression. Techniques such as immunohistochemistry and ELISA were employed for expression analysis in human breast cancer samples. Additionally, electrophoretic mobility shift assays (EMSA) were conducted to assess direct binding interactions between BRCA1 and β-hCG237.
The findings underscore the potential of β-hCG as a therapeutic target in BRCA1-deficient breast carcinomas. Given its elevated expression in aggressive cancer types associated with BRCA1 mutations, targeting β-hCG could lead to novel treatment strategies for patients with this genetic predisposition.
Breast cancer
Breast cancer is the most common cause of cancer-related deaths among women, with approximately 90% of these fatalities linked to the metastasis of cancer cells.
In 2022, there were 2.3 million women diagnosed with breast cancer and 670 000 deaths globally, according to the WHO.
It is the second most prevalent malignant cancer, with the majority of patients succumbing not to the primary tumor but to metastatic spread to distant organs, such as the lungs, liver, and bones.
About 10-15% of breast cancer patients exhibit aggressive disease, leading to tumor metastasis within three years of the initial diagnosis.
