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Developmental Biology - Breast Cancer Epigenetics

We Are What We Eat

Advanced Glycation End products (AGEs) could be slowing down our response to tamoxifen therapy in (ER) positive breast cancers...


Poor diet and lack of exercise are associated with cancer, but the underlying biological mechanisms are still being worked out. However, advanced glycation end products (AGEs) are a link to lifestyle behaviors that increase our breast cancer risk - even lessening the effect of an anti-cancer therapy.
AGE or advanced glycation end products accumulate naturally as the unavoidable result of breaking down nutrients, sugars and fats from what we eat.

Their levels, however, increase when we eat processed foods high in sugar and fat and/or cook foods by grilling, searing and frying.

High AGE levels could be preventing patients with estrogen receptor or (ER) positive breast cancer from responding to tamoxifen therapy, suggest pre-clinical findings from the Medical University of South Carolina (MUSC). The report appears in the journal Breast Cancer Research and Treatment. The MUSC team was led by both David P. Turner PhD, assistant professor at MUSC College of Medicine and member of the Hollings Cancer Center, and Marvella E. Ford PhD, professor, MUSC College of Medicine and associate director of Cancer Disparities at Hollings Cancer Center.

"By showing AGEs in the diet may impact how well breast cancer patients respond to therapy, we can make breast cancer patients aware of their existence. We can then design lifestyle interventions aimed at reducing AGE intake," says Turner.
AGEs cause an imbalance between molecules known as free radicals and antioxidants. This imbalance leads to chronic inflammation promoting development of chronic diseases. Accumulated in our organs, AGEs cause diabetes, Alzheimer's, cardio-vascular disease, arthritis and cancers. Though to date, they have not been studied in depth in cancers.

The work by Turner, Ford and colleagues reveals how elevated levels of AGE lead to continuously activated cell signalling that promotes cell growth or cancer. A key molecule turned in those pathways is the difference between ER positive and ER negative breast cancer. The MUSC team found AGEs actually increase phosphorylation the process that turns on the biological pathway in a protein called estrogen receptor alpha.

Phosphorylation is the process that changes proteins after they've been formed. Using specific enzymes called kinases, a protein can alter its existing pattern using a phosphate group (PO3-4). This phosphate group is usually provided by the ATP energy source carried within a cell.
Adding tamoxifen to cancer cells in a petri dish, prevents their growth. However, adding AGEs causes them to grow again. This could mean patients with high AGEs are less likely to respond to tamoxifen.

Turner's team found that lifestyle intervention through exercise and diet, lowered levels of AGEs in overweight women with non-metastatic ER-positive breast cancer.

Next the researchers will expand their study to determine the effects of AGE intervention on a larger population, while also exploring biological pathways in animal models of breast cancer. Together, these expanded results will reveal more about how how lifestyle intervention affects cancer treatments.

Abstract
Purpose: Lifestyle factors associated with personal behavior can alter tumor-associated biological pathways and thereby increase cancer risk, growth, and disease recurrence. Advanced glycation end products (AGEs) are reactive metabolites produced endogenously as a by-product of normal metabolism. A Western lifestyle also promotes AGE accumulation in the body which is associated with disease phenotypes through modification of the genome, protein crosslinking/dysfunction, and aberrant cell signaling. Given the links between lifestyle, AGEs, and disease, we examined the association between dietary-AGEs and breast cancer.

Methods: We evaluated AGE levels in bio-specimens from estrogen receptor-positive (ER+) and estrogen receptor-negative (ER-) breast cancer patients, examined their role in therapy resistance, and assessed the ability of lifestyle intervention to reduce circulating AGE levels in ER+ breast cancer survivors.

Results: An association between ER status and AGE levels was observed in tumor and serum samples. AGE treatment of ER+ breast cancer cells altered ER? phosphorylation and promoted resistance to tamoxifen therapy. In a proof of concept study, physical activity and dietary intervention was shown to be viable options for reducing circulating AGE levels in breast cancer survivors.

Conclusions: There is a potential prognostic and therapeutic role for lifestyle derived AGEs in breast cancer. Given the potential benefits of lifestyle intervention on incidence and mortality, opportunities exist for the development of community health and nutritional programs aimed at reducing AGE exposure in order to improve breast cancer prevention and treatment outcomes.

Authors
Walter KR, Ford ME, Gregoski MJ, Kramer RM, Knight KD, Spruill L, Nogueira LM, Krisanits BA, Phan V, La Rue AC, Lilly MB, Ambs S, Chan K, Turner TF, Varner H, Singh S, Uribarri J, Garrett-Mayer E, Armeson KE, Hilton EJ, Clair MJ, Taylor MH, Abbott AM, Findlay VJ, Peterson LL, Magwood G, Turner DP.

Acknowledgements
About MUSC
Founded in 1824 in Charleston, The Medical University of South Carolina is the oldest medical school in the South. Today, MUSC continues the tradition of excellence in education, research, and patient care. MUSC operates a 700-bed medical center, which includes a nationally recognized Children's Hospital, the Ashley River Tower (cardiovascular, digestive disease, and surgical oncology), Hollings Cancer Center (a National Cancer Institute-designated center) Level I Trauma Center, and Institute of Psychiatry. For more information visit muschealth.org.

About Hollings Cancer Center
The Hollings Cancer Center at the Medical University of South Carolina is a National Cancer Institute-designated cancer center and the largest academic-based cancer research program in South Carolina. The cancer center comprises more than 100 faculty cancer scientists and 20 academic departments. For more information, visit http://www.hollingscancercenter.org

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Jan 3, 2018   Fetal Timeline   Maternal Timeline   News   News Archive




Stylized image suggesting a link between AGEs and diet. Illustration by Emma Vought,
Medical University of South Carolina.


Phospholid by Wikipedia