̽��ֱ�� of Cambridge - Sara Pensa

‘Exhausted’ immune cells in healthy women could be target for breast cancer prevention

jg533 — Thu, 28 Mar 2024 10:03:44 +0000

Everyone has BRCA1 and BRCA2 genes, but mutations in these genes - which can be inherited - increase the risk of breast and ovarian cancer.

̽��ֱ��study found that the immune cells in breast tissue of healthy women carrying BRCA1 or BRCA2 gene mutations show signs of malfunction known as ‘exhaustion’. This suggests that the immune cells can’t clear out damaged breast cells, which can eventually develop into breast cancer.

This is the first time that ‘exhausted’ immune cells have been reported in non-cancerous breast tissues at such scale - normally these cells are only found in late-stage tumours.

̽��ֱ��results raise the possibility of using existing immunotherapy drugs as early intervention to prevent breast cancer developing, in carriers of BRCA1 and BRCA2 gene mutations.

̽��ֱ��researchers have received a ‘Biology to Prevention Award’ from Cancer Research UK to trial this preventative approach in mice. If effective, this will pave the way to a pilot clinical trial in women carrying BRCA gene mutations.

“Our results suggest that in carriers of BRCA mutations, the immune system is failing to kill off damaged breast cells - which in turn seem to be working to keep these immune cells at bay,” said Professor Walid Khaled in the ̽��ֱ�� of Cambridge’s Department of Pharmacology and Wellcome-MRC Cambridge Stem Cell Institute, senior author of the report.

He added: “We’re very excited about this discovery, because it opens up potential for a preventative treatment other than surgery for carriers of BRCA breast cancer gene mutations.

“Drugs already exist that can overcome this block in immune cell function, but so far, they’ve only been approved for late-stage disease. No-one has really considered using them in a preventative way before.”

̽��ֱ��results are published today in the journal Nature Genetics.

Risk-reducing surgery, in which the breasts are removed, is offered to those at increased risk of breast cancer. This can be a difficult decision for young women to make and can have a significant effect on body image and sexual relationships.

“ ̽��ֱ��best way to prevent breast cancer is to really understand how it develops in the first place. Then we can identify these early changes and intervene,” said Khaled.

He added: “Late-stage breast cancer tends to be very unpredictable and hard to manage. As we make better and better drugs, the tumours just seem to find a way around it.”

Using samples of healthy breast tissue collected from 55 women across a range of ages, the researchers catalogued over 800,000 cells - including all the different types of breast cell.

̽��ֱ��resulting Human Breast Cell Atlas is now available as a resource for other researchers to use and add to. It contains huge amounts of information on other risk factors for breast cancer including Body Mass Index (BMI), menopausal status, contraceptive use and alcohol consumption.

“We've found that there are multiple breast cell types that change with pregnancy, and with age, and it’s the combination of these effects - and others - that drives the overall risk of breast cancer,” said Austin Reed, a PhD student in the ̽��ֱ�� of Cambridge’s Department of Pharmacology and joint first author of the report.

He added: “As we collect more of this type of information from samples around the world, we can learn more about how breast cancer develops and the impact of different risk factors - with the aim of improving treatment.”

One of the biggest challenges in treating breast cancer is that it is not just one disease, but many. Many different genetic variations can lead to breast cancer, and genetic risk interacts with other risk factors in complicated ways.

For example, it is known that the likelihood of breast cancer increases with age, but this risk is greatly reduced by pregnancy early in life. And age-associated risk is greatly increased in carriers of the breast cancer genes BRCA1 and BRCA2.

̽��ֱ��new study aimed to understand how some of these risk factors interact, by characterising the different cell types in the human breast under many different physiological states.

̽��ֱ��researchers used a technique called ‘single cell RNA-sequencing’ to characterise the many different breast cell types and states. Almost all cells in the body have the same set of genes, but only a subset of these are switched on in each cell – and these determine the cell’s identity and function. Single cell RNA-sequencing reveals which genes are switched on in individual cells.

“Breast cancer occurs around the world, but social inequalities mean not everyone has access to treatment. Prevention is the most cost-effective approach. It not only tackles inequality, which mostly affects low-income countries, but also improves disease outcome in high-income countries,” said Dr Sara Pensa, Senior Research Associate in the ̽��ֱ�� of Cambridge’s Department of Pharmacology and joint first author of the study.

Breast tissue samples were provided by the Breast Cancer Now tissue bank.

̽��ֱ��research was primarily funded by the Medical Research Council and Cancer Research UK.

Reference: Reed, A.D. et al: ‘A human breast cell atlas enables mapping of homeostatic cellular shifts in the adult breast.’ Nature Genetics, March 2024. DOI: 10.1038/s41588-024-01688-9

Researchers at the ̽��ֱ�� of Cambridge have created the world’s largest catalogue of human breast cells, which has revealed early cell changes in healthy carriers of BRCA1 and BRCA2 gene mutations.

We’re very excited about this discovery, because it opens up potential for a preventative treatment other than surgery for carriers of BRCA breast cancer gene mutations.

Walid Khaled

Angiola Harry on Unsplash

Woman holds pink breast cancer awareness ribbon. Credit angiola-harry-unsplash

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Changes can be detected in BRCA1 breast cells before they turn cancerous

jg533 — Tue, 09 Mar 2021 09:17:18 +0000

̽��ֱ��study, funded by Cancer Research UK, showed that before becoming cancerous, breast cells with the BRCA1 gene mutation undergo changes similar to those normally seen in late pregnancy.

Although this is early research, in the future doctors could screen women with BRCA1 mutations to monitor changes to their breast cells, which could help inform who might benefit from preventative surgery, and to give reassurance to those who can wait.

BRCA1 mutations significantly increase the risk of developing breast cancer at a younger age. Many women who discover they carry the faulty gene choose to have a preventative mastectomy. This involves surgically removing some or all of the healthy breast tissue, which can reduce but not eradicate the risk of developing breast cancer.

Not all women who have BRCA1 mutations will go on to develop cancer so for some, this life-changing surgery may be unnecessary, or could at least be delayed until early warning signs are spotted.

Researchers led by Karsten Bach and Dr Sara Pensa at the ̽��ֱ�� of Cambridge wanted to develop a method to detect the early changes occurring in BRCA1-affected breast cells indicating that they are progressing towards breast cancer.

̽��ֱ��team analysed the mammary tissue of 15 mice at various ages carrying the BRCA1 mutation to look for changes in the tissue that were happening before the mice developed tumours.

̽��ֱ��researchers found that having a BRCA1 mutation triggered certain pathways to be switched on in a type of stem cell called a luminal progenitor breast cell that are only activated during pregnancy. These messages tell the progenitor cell to turn into alveolar cells, which make up the chambers in the breast where milk-production takes place during late pregnancy.

Karsten Bach, co-author on the study and PhD student at the Department of Pharmacology and Cancer Research UK Cambridge Institute, said: “We thought we’d been given the wrong mice at first. Then we realised that having the BRCA1 mutation seemed to cause the cells in their breast tissue to behave as if the mouse was pregnant.

“ ̽��ֱ��changes we saw happened very early on before any tumours were detected, so we reasoned that markers of these cellular changes could be used to monitor people who we know are at increased risk for breast cancer.”

Next the team analysed breast cells from 12 women who had a BRCA1 mutation and had undergone a preventative mastectomy.

Surprisingly, the team found that only 4 out of the 12 women had detectable levels of these markers of early stages of tumour initiation. This suggests that the majority of women may have been at lower risk of already being on the path towards tumour development when they had the surgery.

Dr Sara Pensa co-author and Senior Research Associate at the Department of Pharmacology and Wellcome-MRC Stem Cell Institute, said: “One of the mysteries surrounding BRCA gene mutations is how they increase a woman's risk of cancer so dramatically in the breast tissue, as opposed to say the kidneys or lung. It seems that certain pathways in breast cells that are usually switched on by hormones during pregnancy are triggered by BRCA1 mutations and cause the cells to grow out of control.”

Although this is early work and larger clinical trials will be needed, the researchers hope to build on their findings and develop a blood test to detect the early changes occurring in BRCA1 breast cells.

Researchers say in the future, doctors could screen at-risk women with BRCA1 mutations, and help them have informed conversations with women about their risk, guide decisions about preventative surgery, and to give reassurance to those considered not to need surgery at that time.

Michelle Mitchell, chief executive for Cancer Research UK, said: “ ̽��ֱ��discovery of BRCA mutations gave much needed answers to families with a strong history of breast cancer. However, for women that carry the BRCA mutation that are yet to develop breast cancer, they face an incredibly difficult dilemma.

“This is fascinating research, and we look forward to seeing the next steps, which could mean in the future, doctors could detect if women carrying these mutations have breast cells that are behaving differently. This could make a world of difference, as they may not need preventative surgery until later in life, or even at all.”

Reference

Bach K. & Pensa S. et al.'Time-resolved single-cell analysis of Brca1 associated mammary tumourigenesis reveals aberrant differentiation of luminal progenitors.' Nature Communications, March 2021.

Original press release by Cancer Research UK (CRUK).

Researchers may have found the earliest changes that occur in seemingly healthy breast tissue long before any tumours appear, according to a new study published today in the journal Nature Communications.

It seems that certain pathways in breast cells that are usually switched on by hormones during pregnancy are triggered by BRCA1 mutations and cause the cells to grow out of control.

Sara Pensa

slgckgc on Flickr

Mammogram image

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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