– Stephen Mc Neil

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From: medicalxpress.com

Researchers from Drexel University’s College of Medicine have identified a critical metabolic vulnerability in breast cancer that has spread to the brain, offering a promising new therapeutic target for a disease with few effective treatment options. When this weakness is targeted, cancer cells undergo cell death. The study found that an enzyme called acetyl-CoA synthetase 2, or ACSS2, enables brain metastatic breast cancer cells to evade ferroptosis, a form of iron-dependent cell death. Importantly, this is the first study to demonstrate that breast cancer cells growing in the brain must suppress ferroptosis in order to survive. The findings were recently published in the journal Cancer Research.

In the study, researchers from Drexel University’s College of Medicine and Sidney Kimmel Cancer Center—through the Sidney Kimmel Comprehensive Cancer Center (SKCCC) Research Consortium—discovered that breast cancer cells that spread to the brain rely on a specific metabolic pathway that converts acetate into a form of energy that tumors need to grow, but which also protects from ferroptosis. Taking this a step further, the group found that blocking this pathway prevents cancer cells from surviving in the brain and small molecules targeting ACSS2 can also induce ferroptosis and shrink tumors in preclinical models.

About 10-15% of stage IV breast cancer patients develop brain metastasis, which occur when cancer cells spread from the breast to the brain. Nearly eight out of 10 of these patients face end-stage disease within a year of diagnosis. Brain metastases develop when cancer cells separate from the primary breast tumor and travel along the bloodstream or lymphatic system, ultimately forming new tumors in the brain. Symptoms can include painful headaches, weakness and seizures, cognitive decline, among other issues.

Treating breast cancer that has spread to the brain remains especially challenging. The blood-brain barrier, a protective shield that keeps harmful substances from entering the brain, also prevents many cancer therapies from effectively reaching tumors. While radiation and surgery may help alleviate symptoms and reduce the tumor size, these options are ineffective and come with serious side effects impacting quality of life.

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– Noelle Wingate

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From: sdsu.edu

A treatment for the most common type of breast cancer may already exist. As reported in a December paper in Nature Communications, San Diego State University researchers who were part of an international study believe they found one.

Associate professor of biology Svasti Haricharan initially approached her early research wondering, “Why do some people get cancer and other people don’t? Something about it feels so unfair.” As her career progressed she realized there was another way to look at it.

“The right question is, ‘Why is it that all of us don’t get cancer?’”

Our cells mutate all the time: fortunately, everyone has specialized proteins that constantly scan DNA, targeting and killing mutated cells to ensure they don’t become cancerous. But some people who do develop cancer are missing a specific DNA repair protein called MLH1, which causes them to become resistant to standard therapies.

To understand why, Haricharan’s lab honed in on the most common type of breast cancer: estrogen receptor positive (ER+) breast cancer, which makes up 80% of breast cancer cases worldwide and is the most common cause of breast cancer-related death.

Her group found that in some patients, MLH1 is not missing, but located in the wrong part of the cell, which leads to even more robust resistance to treatment.

“It should be in the nucleus, where the DNA is, but we were seeing it in the cytoplasm, where there is no DNA,” Haricharan said.

With 30% of all breast cancer patients resistant to standard therapies and limited knowledge on why and which, if any, of the few available alternative treatments will work, most of these patients do not have positive outcomes.

Currently, ER+ breast cancer patients are treated with standard endocrine therapies that boost MLH1 levels in the nucleus and kill the damaged, cancerous cells. However, many become resistant to this treatment so after three to five years, during which the tumor has grown and spread to other parts of the body, they are given a targeted therapeutic called CDK4/6 inhibitors as a last resort.

In other cases, patients appear to respond well to treatment for years. However, a group of sleeper cells subtly remain, learning how to combat standard treatments, and up to 20 years later, patients relapse with a tumor that is more aggressive and resistant to standard therapies. At that point, even CDK4/6 inhibitors can be ineffective. Physicians are unable to predict which patients carry these sleeper cells.

But Haricharan’s lab made a finding that points toward a new treatment, pending additional tests.

Their study showed that, for ER+ breast cancer cells where MLH1 is located in the wrong place, an early intervention with CDK4/6 inhibitors in most cases doesn’t just prevent tumors from growing, but shrinks them.

“We found that when we have this cytoplasmic mislocalization protein, although patients are resistant to standard therapies, they are sensitive to CDK4/6 inhibitors, which is safe, available and FDA approved for certain types of breast cancer,” Haricharan said. “This is a new indication for patients who can be eligible for that therapy, and would likely respond better to that than the standard therapy alone.”

Haricharan’s team is now organizing a clinical trial to further test this theory which they think can boost survival rates.

“The reason we are excited about it is that the diagnostic already exists and is clinically certified, and the therapeutic already exists and is FDA approved,” she said. “This is just repurposing an existing drug to a new patient population, which means it can be given to patients right now, so to speak.”

Haricharan’s study also seems to suggest the sleeper population could be the cells with MLH1 in the cytoplasm instead of the nucleus.

“Even a very small subset of cells can likely induce resistance years down the line,” she said. “That is why we think it is really important to give the intervention early on, so you don’t let the sleeper population evolve and become more dangerous, but try to kill it early on so your resistance probability is significantly decreased.”

In addition to SDSU, the 18 listed authors of the study included researchers from UCSD Moores Cancer Center, Sanford Burnham Prebys Medical Discovery Institute (La Jolla), Temple University, European Institute of Oncology IRCCS (Milan, Italy), University of Milan, and Rady Children’s Institute for Genomic Medicine, San Diego.

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I was recently reminded of that when I was chatting with a friend who was dealing with her own cancer diagnosis. I remember making a conscious effort to make her smile and perhaps even laugh. Here she was, facing her own battle and experiencing all of the fear that comes with the not knowing. It’s the not knowing how bad your situation might be. It’s the not knowing about what surgery will be like and whether you will have to have chemotherapy. It’s the not knowing whether you have the strength to deal with everything ahead of you. It’s the not knowing with whom you are going to share your diagnosis and how you will share it. The list goes on and on. And it is in that moment when you need to have someone on your side that is willing to help you find ways to put a smile on your face.

It was in this vein that I chose to share with my friend about my lessons on how to deal with my drain tubes after surgery. I couldn’t help but describe all of maneuvering and manipulations I went through in order to keep those things hoisted up so that they wouldn’t be a hassle. After all, at that time I don’t even know if they had those cute little shirts that you can get now with pockets to hold the receptacles in place. So, safety pins holding them in place on the inside of my T-shirt was my method of dealing with them. Of course, my description had her laughing out loud and when it came time for her to deal with her own drain tubes, she had a visual of my demonstration that made her laugh and made it so much easier for her to deal with what I thought was one of the worst parts of the follow-up to surgery.

I know how hard it is to keep a positive attitude when you have just been diagnosed with breast cancer but perhaps my little trick might help you or someone you know. Whenever I felt like I was focusing all of my thoughts and energy on the cancer journey, I started smiling. Yes, I would smile. And what I learned is that when you are smiling, your heart and mind start smiling, too. Your energy changes completely. You just can’t feel down or sad with a smile on your face. If I felt like the smile was starting to fade, I would start to think about something that would actually make me laugh out loud and even if the giggling made me hurt a little more, the pain quickly faded when I was no longer focused on it.

So I suggest that you give a smile a try whenever your thoughts start to travel in the wrong direction. If you have someone else around, try to laugh with him or her about something – anything. It is amazing how your spirits will be lifted. And if you do this every time that you start focusing on something negative, you will soon create a new habit for yourself that will completely turn your life around. Just remember, a little smile always goes a long way!

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– Noelle Wingate

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From: oncodaily.com

Breast cancer is the most common cancer in women globally and shows significant heterogeneity. This heterogeneity is present at inter- and intratumoural levels and influences disease progression, therapeutic response along with clinical outcomes. Intertumoural heterogeneity arises from molecular and genomic differences in patients with distinct clinical subtypes and variable prognosis. Intratumoural heterogeneity comes from interactions between tumour microenvironmental factors and intrinsic cancer cell properties like genetic and epigenetic diversity, transcriptomic diversity, proliferative capacity, and stemness. Cancer cell plasticity allows dynamic reprogramming and helps in adapting to environmental pressure which promotes survival and evolution. Processes like clonal evolution, epithelial- mesenchymal transition (EMT), and interclonal cooperation further stimulate tumour progression, metastasis, and resistance to therapy. Heterogeneity is a major hurdle in designing treatment modality, mainly for metastatic breast cancer.

Molecular Subtypes and Therapy Resistance

Breast cancer shows intratumoural heterogeneity across subtypes like luminal A/B, HER2- enriched, basal-like, and claudin-low, fueled by clonal evolution and non-genetic cell-state plasticity. Tumour cells dynamically interconvert subtypes, influenced by the tumour microenvironment (TME) including cancer-associated fibroblasts (CAFs), macrophages, immune cells, and hypoxia, promoting metastasis and resistance. Single-cell RNA-seq reveals hierarchical structures with multiple cancer stem cell (CSC) populations undergoing EMT and mesenchymal-epithelial transition (MET). For instance, ER+/HER2− primaries shift to HER2+ in metastases. ITH enables therapy escape, as seen in residual disease post- neoadjuvant treatment showing increased plasticity markers. Hybrid epithelial/mesenchymal states enhance invasiveness and stemness.

Cancer stem cells (CSCs) and Plasticity

Cellular plasticity in breast cancer drives tumour progression, metastasis, and therapy resistance through EMT and CSC properties. Cells toggle phenotypes without genetic changes, navigating the metastatic cascade-from invasion and circulation survival to colonization-via hybrid epithelial-mesenchymal states and stemness. Pathways like MAPK, PI3K/AKT, STAT3,Wnt, and Notch regulate this adaptability, worsened by signals from the microenvironment. Targeting plasticity can be promising against resistant metastatic disease. Breast cancer heterogeneity due to CSCs and linked to EMT is determined to be a key factor in cancer relapse and metastasis. This again compels for the need of targeted therapies. Research confirms breast cancer stem cells (BCSCs) are responsible for tumour initiation, progression, metastasis, resistance, and recurrence. Advances in identifying BCSCs and understanding their signaling pathways have enabled targeted therapies that disrupt quiescence, overcome treatment resistance, and inhibit stemness mechanisms.

Tumour microenvironment (TME)

The TME is now recognized as a critical contributor to breast cancer heterogeneity. Tu et al. (2025) analysed tumour microenvironments in 14,837 breast cancers and identified 7 distinct ‘TME types’. These TME types can independently predict clinical outcomes. They concluded B cell lineages as important prognostic factors. Their depletion was associated with metastasis, suggesting TME composition can guide personalized treatment strategies.

Diagnostic Challenges and Emerging Therapeutic Opportunities

Shihao Sun et al., 2025 conducted multi-scale analysis of triple-negative breast cancer, revealing significant cellular heterogeneity. They identified maternally expressed gene 3- positive (MEG3+) pre-cancer-associated fibroblasts subgroup and found BRCA1 wild-type patients had increased T-cell exhaustion and dendritic cell tolerance compared to BRCA1 mutants. They proposed Interferon-stimulated gene 15 (ISG15) as an immunoregulatory biomarker and developed a machine learning-based predictive system for immunotherapy response forecasting, though further validation is needed.

Recent integrative analyses further stress on the prognostic relevance of tumour microenvironment heterogeneity. A comprehensive bioinformatics and single-cell RNA sequencing study developed a tumour microenvironment related prognostic model that can classify breast cancer patients into different risk groups and also predict responsiveness to immunotherapy. The study identified endothelial cells as high-risk cellular populations associated with poor prognosis and demonstrated variations in drug sensitivity across cellular subtypes, highlighting the potential of TME-based molecular signatures for guiding personalized therapeutic strategies.

There are significant diagnostic challenges due to high inter-observer variability and low assay sensitivity when differentiating between HER2-low and HER2-null subtypes in heterogeneous tumours. This problem can be solved by using antibody-drug conjugates like trastuzumab deruxtecan as they can kill neighbouring cancer cells even when they vary in HER2 expression levels due to the bystander killing effect.

Conventional chemotherapy fails in many cases of triple-negative breast cancer (TNBC) mainly due to high heterogeneity, drug resistance and lack of specific targets. Molecular typing systems like Lehmann, Burstein, and Fudan typing have showed various subtypes with different molecular characteristics and treatment responses. This can help in the development of targeted therapies like PARP inhibitors, PI3K/AKT/mTOR pathway inhibitors, and antibody-drug conjugates for more precise and personalized treatment. Liquid biopsy and multi-omic biomarkers have transformed breast cancer diagnosis. These techniques are less invasive and real-time monitoring of ctDNA, CTCs, exosomes, and proteomic profiles is possible. These methods along with the integration of AI provide early detection, better therapy guidance and relapse prediction compared to traditional tissue biopsies. Challenges presented are standardization, costs, and inequality in acess.

Conclusion:

Clinical trial designs need to take into consideration tumour evolution and its innate complexity from the beginning. Multimodal molecular profiling, liquid biopsies, and dynamic treatment selection provide real-time monitoring of tumour changes and thus can help in adaptive therapy. Understanding biological heterogeneity in breast cancer is now essential for advancing personalized adaptive oncology to significantly improve long-term patient outcomes.

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– Lailah Gifty Akita

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From: medscape.com

For women with breast cancer, vitamin D levels around the time of diagnosis might be related to long-term survival, a large prospective study showed.

Over a median of 12 years, women with sufficient vitamin D levels at breast cancer diagnosis had a 24% boost in overall survival compared to those with a vitamin D deficiency, the study found.

They also showed a 33% relative reduction in cardiovascular risk factors, such as diabetes and dyslipidemia.

“Correction of vitamin D deficiency, even during the time of diagnosis, may represent a simple local strategy to improve both cancer survival outcomes and cardiovascular risk factors in patients with breast cancer,” study co-author Alfredo Chua, Jr, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, New York, told Medscape Medical News.

The study was published online in the Journal of the National Comprehensive Cancer Network.

The findings add to a body of research hinting that vitamin D deficiency — a common issue among US women with breast cancer — may worsen patients’ outcomes. Cohort studies have found a dose-response relationship between vitamin D status and overall survival in breast cancer. Meanwhile, a recent analysis from the Women’s Health Initiative trial found that participants who took vitamin D plus calcium were 7% less likely to die of any cancer over 22 years than those given placebos.

However, the supplement group also showed a comparable increase in cardiovascular mortality.

So for the new study, Chua and his colleagues looked at the relationship between vitamin D status and both breast cancer and cardiovascular outcomes.

The researchers tested serum 25-hydroxyvitamin D levels in a prospective cohort of almost 4000 patients at or near the time of breast cancer diagnosis. Vitamin D levels were deemed sufficient at 30 ng/mL or higher; insufficient at 20-29.9 ng/mL; and deficient at less than 20 ng/mL. The median follow-up was 12.2 years.

Overall, the study found that sufficient vitamin D status was associated with better survival vs deficiency (hazard ratio [HR], 0.76; P = .005), after adjustment for age, BMI, physical activity, smoking, race and ethnicity, tumor characteristics, and treatment types.

Sufficient vitamin D was also linked to improved second primary cancer-free survival (HR, 0.75; P = .003) and disease-free survival (HR, 0.82; P = .05).

All of those trends were restricted to patients with stage II or higher disease — most likely because of the generally good prognosis for patients with stage I breast cancer, Chua noted.

As for cardiovascular health, women with sufficient vitamin D had a lower likelihood of any incident cardiometabolic risk factor (subdistribution HR, 0.67; P < .001). They also showed a trend toward lower risk for cardiovascular disease, although no significant decline in risk for cardiovascular mortality was observed.

Azeez Farooki, MD, an endocrinologist at Memorial Sloan Kettering Cancer Center in New York City, reviewed the study for Medscape Medical News. He described it as “probably one of the best ones that have been done” on the relationship between vitamin D status and breast cancer survival.

Farooki said that in his own practice, where he sees patients whose bone health has been harmed by chemotherapy or radiation, he routinely checks vitamin D status.

But he said, the new findings alone are not enough to warrant testing vitamin D levels in all women diagnosed with breast cancer — or to offer them “definitive” advice on using supplements.

Farooki noted that while the researchers adjusted for various confounders, there may be other explanations for why women with sufficient vitamin D had better outcomes.

“What we really need is a randomized clinical trial to prove causality,” he said.

Chua agreed that such a trial is needed, especially since his team only tested for vitamin D levels at one point in time.

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– Lailah Gifty Akita

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