Tracing the Mutation Trail of Breast Cancers
The new study expands our understanding of the route mutations take before cells develop into breast cancers.
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The process of mutations that lead to breast cancer has been uncovered in a new study, published in Nature.
Tracking breast cancer development
Breast cancer is one of the most common cancer types, with 2.3 million women diagnosed with breast cancer worldwide in 2020.
Events called driver mutations – which occur in cells that are already cancerous and drive cancer growth – have been extensively studied in breast cancer cells. However, these do not paint the full picture of the mechanisms leading up to cancer formation from healthy cells.
Evidence of normal breast cells carrying mutations commonly found in cancer has been uncovered in recent studies, but our understanding of the route these mutations take before cells develop into cancer is still poor.
"Normal-looking tissues may already contain numerous populations of non-cancer cells – or clones – that have acquired mutations in cancer-related genes," said study co-author Tomomi Nishimura.
To study the evolutionary histories of breast cancers, researchers from Kyoto University investigated samples of non-cancerous and cancerous cells with a driver mutation known as der(1;16), which is found in around 20% of breast cancers. “Through phylogenetic analyses, we successfully traced the evolution of breast cancer and precursor lesions, from the acquisition of initial driver alterations to the development of clinically diagnosed disease,” they write in the paper.
A new understanding of breast cancer formation
The researchers analyzed breast cancer organoids – lab-grown “mini-organs” that mimic some of the characteristics of the real organ – and both normal and cancerous breast tissue to study the history of breast cancers.
According to their first analysis, mammary epithelial cells – whose main function is to produce milk – accumulate approximately 20 mutations every year until menopause, but that this slows down afterward.
After examining the similarities and differences in the mutations of both cancer and non-cancer lesions, the team reconstructed an evolutionary tree to visualize the unique pattern of cancer evolution.
They investigated the genetic relationship between breast cancer, its surrounding lesions and normal epithelial cells. This allowed them to map the cancer’s expansion, identifying cells of multiple origins that manifested on average by the age of 30 that would subsequently develop into breast cancer.
The study also sheds light on the role of estrogen in breast cancer, as around 70% of breast cancers are estrogen-sensitive: "Additionally, our results suggest that estrogen influences mutation accumulation in mammary epithelium, which correlates with our discovery of decreased accumulation after childbirth," said Seishi Ogawa, senior author of the study.
“Our study brings us closer to exposing the clinical profile of estrogen-sensitive breast cancer, particularly in pre-menopausal women, potentially aiding cancer risk monitoring and prevention,” Ogawa added.
Reference: Nishimura T, Kakiuchi N, Yoshida K, et al. Evolutionary histories of breast cancer and related clones. Nature. 2023;620(7974):607-614. doi: 10.1038/s41586-023-06333-9
This article is a rework of a press release issued by Kyoto University. Material has been edited for length and content.