An analysis of genomic and gene expression data has shown that the pro-survival protein myeloid cell leukemia 1 (MCL-1) is frequently is overexpressed in many cancers including breast cancer.[1][2] Various studies have demonstrated an association between high levels of the anti-apoptotic BCL-2 family member MCL-1 and poor prognosis in specific subtypes of breast cancer including triple-negative breast cancer, an aggressive form that lacks targeted treatment options. [1][3]

A new study confirms that MCL-1 could be targeted with a new type of drug that is already being tested for other cancers, new research reveals.[3]

Apoptosis
MCL-1 helps breast cancer cells survive, by hindering cells’ natural ability to die through a process called apoptosis, and proves that breast cancer tumors in fact rely on this protein to help them grow more aggressively, by blocking this natural cellular self-destruct function. The research was funded by Breast Cancer Now, in partnership with the Scottish Government’s Chief Scientist Office, and took place at the University of Glasgow.

Apoptosis is a natural process by which unwanted, harmful, or damaged cells are removed from our bodies and play an important part in our growth and development. Apoptosis can also play a key role in preventing cancer; however, cancer cells will often evolve to avoid this process.

Current breast cancer treatments target a range of proteins, but this study could be an important step towards targeting MCL-1 as a way to treat people with breast cancer and developing urgently needed new treatments for the disease. The study has also discovered that breast cancer stem cells, which are thought to be responsible for the disease spreading and becoming resistant to treatments, are especially dependent on MCL-1 for growth and survival.

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Excitingly, the study suggests a new type of drug called BH3 mimetics, which targets the MCL-1 protein, could be used to ‘kick-start’ apoptosis in breast cancer cells to help treat people with breast cancer, and slow the growth of tumors. BH3 mimetics are already undergoing clinical trials for some blood cancers. While further testing is needed, this new study presents a strong case to test this emerging new therapy in breast cancer too.

This new research, published in Nature’s Cell Death & Differentiation, was led by Professor Stephen Tait D.Phil and Kirsteen Campbell MD., at the Institute of Cancer Sciences at the University of Glasgow, in collaboration with Professor Karen Blyth from the Beatson Institute for Cancer Research, Glasgow.

In experiments with mice, the team showed that MCL-1 is critical for the growth and survival of breast cancer. When MCL-1 was removed from existing breast tumors in mice, it led to tumors shrinking. The results suggest that targeting MCL-1 with drugs could work as a treatment strategy for breast cancer.

The team then tested whether BH3 mimetic drugs, targeting the MCL-1 protein, could stop the growth of breast cancer in mice. The results showed that the growth of tumors was significantly slowed down and suggest that with further testing, BH3 mimetic drugs have the potential to treat people affected by breast cancer.

The study also found that the absence of the BAX and BAK proteins – which are essential for apoptosis – targeting MCL-1 did not slow the growth of tumors. This strongly suggests that MCL-1, which has more than function, is helping breast cancer survive specifically by stopping apoptosis.

“Our study further highlights the importance of MCL-1 protein in breast cancer. Our demonstration that MCL-1 acts in breast cancer by keeping cells alive (as opposed to other MCL-1 functions) is important because drugs that target MCL-1 survival function are now in clinical development,” explained Professor Stephen Tait D.Phil. at the Institute of Cancer Sciences at the University of Glasgow

“The next steps will be to determine the effectiveness of MCL-1 targeting drugs that are in clinical development, to treat breast cancer in combination with existing therapies,” Tait added.

Confirm the role of MCL-1
“It’s hugely exciting that this study could confirm the role that the MCL-1 protein plays in allowing breast cancer cells to survive and grow. With this understanding, we can now explore targeting the protein with drugs that are already being tested for treating other types of cancer. Said Simon Vincent, Ph.D., Director of Research, Support, and Influencing at Breast Cancer Now.

“With around 55,000 women being diagnosed with breast cancer every year in the UK, we urgently need to find new ways to treat people and prevent deaths from this devastating disease. As such, while further research is needed, we hope this study leads to new and effective treatments being available for people affected by breast cancer.”

“We’re hugely proud to have funded this exciting discovery, especially at a time when we are all too aware of the profound effects the COVID-19 pandemic has already had on our world-class research. We are now less able to fund new research that could transform the lives of people affected by breast cancer and this is why now, more than ever, we need your support so we can continue to bring hope for the future through our research,” Vincent concluded.

Reference
[1] Campbell KJ, Dhayade S, Ferrari N, Sims AH, Johnson E, Mason SM, Dickson A, Ryan KM, Kalna G, Edwards J, Tait SWG, Blyth K. MCL-1 is a prognostic indicator and drug target in breast cancer. Cell Death Dis. 2018 Jan 16;9(2):19. doi: 10.1038/s41419-017-0035-2. PMID: 29339815; PMCID: PMC5833338.
[2] Campbell KJ, Tait SWG. Targeting BCL-2 regulated apoptosis in cancer. Open Biol. 2018 May;8(5):180002. doi: 10.1098/rsob.180002. PMID: 29769323; PMCID: PMC5990650.
[3] Campbell KJ, Mason SM, Winder ML, Willemsen RBE, Cloix C, Lawson H, Rooney N, Dhayade S, Sims AH, Blyth K, Tait SWG. Breast cancer dependence on MCL-1 is due to its canonical anti-apoptotic function. Cell Death Differ. 2021 Mar 31. doi: 10.1038/s41418-021-00773-4. Epub ahead of print. PMID: 33785871.

Featured image: A doctor examines a mammogram snapshot of the breast of a patient. Photo courtesy: © 2016 – 2021 Fotolia/Adobe. Used with permission.

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