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Published in final edited form as: J Young Womens Breast Cancer Health. 2024 Oct 18;1(1-2):13–19. doi: 10.4103/ywbc.ywbc_11_24

Rising Breast Cancer Rates in Younger Women: Could Dietary Advanced Glycation End Products Be the Missing Link?

Gowtami A Panguluri 1, Victoria J Findlay 1
PMCID: PMC13624866  NIHMSID: NIHMS2211426  PMID: 42819781

Abstract

The incidence of breast cancer is increasing among young women, who are at higher risk of aggressive cancer-related deaths. Lifestyle factors, especially diet, are known to be changeable risk factors that can affect cancer development. This review focuses on the published literature connecting dietary advanced glycation end products (AGEs) and the risk of breast cancer, particularly in the adolescent and young adult (AYA) population. To support our analysis, we collected and synthesized data from sources such as PubMed, the SEER database, the American Association of Food and Nutrition Guidelines, and the World Health Organization publications within the last 15 years. AGEs are mainly found in ultra-processed foods, as well as in foods high in fat and sugar, which are common in the Western diet. AGEs are also created through nonenzymatic glycoxidation during food cooking at high temperatures. AGEs have been linked to cancer progression through the receptor for AGE, which can activate inflammatory and oxidative stress pathways that support tumor formation. Epidemiological studies and preclinical models have indicated that a high dietary intake of AGEs is correlated with an elevated risk of developing breast cancer and poorer survival outcomes for women. While the connection between AGEs and breast cancer risk is evident, there is a lack of research focusing on the AYA population. This highlights the necessity for further investigation to fully comprehend the impact of dietary AGE consumption during formative years on the rising incidence of breast cancer in the AYA population. We want to highlight the significance of cancer prevention methods. This includes initiatives to decrease the intake of dietary AGEs during puberty, when simultaneously raising awareness and providing education on the significance of adopting healthy dietary practices and engaging in regular physical activity. These measures could be effective in reducing the risk of breast cancer among young women worldwide.

Keywords: Adolescent and young adults, advanced glycation end products, breast cancer, diet, lifestyle, nutrition

Graphical Abstract

graphic file with name nihms-2211426-f0001.webp

In Brief, eating foods high in advanced glycation end products (AGEs) during puberty may raise the risk of developing breast cancer and could be linked to the higher occurrence of breast cancer in adolescents and young adults (AYAs). The authors believe that it is important to focus on proactive measures such as regular physical activity, education, and dietary interventions in young women to reduce this risk.

Breast Cancer in Young Women

The adolescent and young adult (AYA) population is a distinct demographic characterized by their age range of 15–39 years.[1] While just 5.6% of breast cancer cases are detected in individuals under the age of 40 years, this specific age group contributes to 15% of the total person-years of life lost due to breast cancer in the US.[2] In 2024, there are estimated 84,100 new cancer cases among AYAs,[3] accounting for 4.2% of all new cancer cases, as well as 8890 cancer-related deaths, accounting for 1.5% of all cancer fatalities. Breast cancer is one of the most common cancer types in AYA, accounting for 15% of new cancer cases, and not surprisingly accounts for the highest mortality rate in cancer in AYA. The incidence and mortality rates also differ by race and gender, with non-Hispanic White women having higher rates of incidence than non-Hispanic Black women (103.6 and 79.3 per 100,000, respectively). In comparison, mortality rates for non-Hispanic Black women are higher than non-Hispanic White women (12.1 and 9.0 per 100,000, respectively), similar to what we observe in adult female populations. SEER statistics clearly show that cancer incidence is steadily rising in the AYA population. Although survival rates are increasing and mortality rates are decreasing in this population, survivorship is an important component of their care.

In 2024, the US is predicted to have 310,720 new cases of invasive breast cancer, making it the most commonly diagnosed cancer, and the second leading cause of mortality among women with cancer.[4] Since 2004, there has been a notable increase in the incidence of invasive breast cancer among AYA women in the US, whereas the incidence is declining among older women.[5] AYA breast cancers were also documented to be more aggressive and are more often detected at more advanced stages in comparison to older women, which leads to worse survival rates.[6] Furthermore, there is a 39% higher likelihood of mortality among AYAs with early-stage illness compared to older patients.[7]

Globally, there were an estimated 1.2 million cancer cases diagnosed and almost 400,000 deaths among AYAs reported in 2019. Of note, breast cancer in AYAs stands out as the highest, with a 10.6% share, of cancer types contributing to the global disability-adjusted life-years (DALYs) burden in AYAs.[8] Conversely, the global incidence of breast cancer has decreased significantly in the elderly population, with a fall of 26% among those aged 90 years or more and a decline of 12%–18% in the age groups of 60–69 and 50–59 years.[9] The burden and outcomes of breast cancer can vary dramatically among areas, with socioeconomic variables playing a key role. AYA patients in high-income countries (HICs) benefit from advances in early identification/screening and comprehensive treatment choices, which help explain their comparatively good survival rates. However, in low–middle-income countries (LMICs), AYAs face considerable obstacles due to limited healthcare resources, including the absence of early detection/screening programs and insufficient treatment facilities.[10] Over 70% of individuals with breast cancer are detected at the first stages of the disease (Stage 1 or 2) in HICs compared to 20%–50% of cases being identified as advanced breast cancers in LMICs.[11] Recent studies by Xu et al.[12] demonstrated a surge in the incidence of breast cancer among young women in the US aged 20–49 years. Despite a decline in breast cancer mortality among specific populations of young women, for example, White populations, there has been a gradual increase among African American and Hispanic populations among young women.[13] In the US, women under the age of 40 years comprise approximately 4%–5% of newly diagnosed Breast Cancer patients compared to 13% in Asia.[14] Globally, substantial data are indicating that Breast Cancer is undoubtedly the primary cause of cancer-associated mortality among young women under the age of 45 years, imposing an enormous challenge and burden in developing nations in contrast to industrialized countries, resulting in a disproportionate number of young women succumbing to this kind of cancer annually.[15]

Dietary Guidelines for Cancer

The American Cancer Society advises following a diet incorporating plant-based foods, nonstarchy vegetables, carotenoid-rich vegetables, and calcium-rich foods when reducing or eliminating processed carbohydrates, animal products, and alcohol.[16] Excessive consumption of a Western diet rich in saturated fats, which are found in red meat and many dairy products, has been associated with an increased risk of breast cancer.[17] Studies from Castelló et al.[18] showed women consuming a Western dietary pattern had a higher risk of developing breast cancer, especially among postmenopausal women with estrogen receptor-positive (ER+) or progesterone receptor-positive human epidermal growth factor receptor 2-negative (HER2−) tumors. Additional supporting studies include EpiGEICAM[19] and MCC-Spain,[20] which also identified an elevated risk of breast cancer associated with the consumption of a Western diet, particularly among premenopausal women.[19] The Global Burden of Diseases, Injuries, and Risk Factors Study found that metabolic and behavioral risk factors, such as a diet that lacked in nutrition (low in milk, whole grains, and fruits), accounted for 5.1% of the risk for breast cancer and other cancers in women.[21] The 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention guidelines stress the need to follow a nutritious diet that includes sufficient amounts of whole grains, vegetables, fruits, and legumes when restricting the intake of common components of the Western diet such as red and processed meats, fast meals, and sugary beverages.[22] This dietary approach is essential to minimize the risk of developing cancer. Studies found that AYA cancer survivors who follow a Western dietary pattern and do not strictly adhere to the 2018 WCRF/AICR recommendations are more likely to experience a recurrence of breast cancer.[23]

Eating Trends in Adolescents and Young Adults

Dietary patterns among AYA’s are shaped by several variables like socioeconomic status, physical activity, cultural standards, social media impact, and individual preferences.[24] According to Qutteina et al.’s study,[25] AYA’s dietary patterns are marked nutrient deficient (foods low in fruits and vegetables) and rich in sugary and savory snacks that fail to meet the dietary guidelines, increasing risk for cancer. A study conducted among AYA cancer survivors used self-reported questionnaires to investigate the impact of modifiable dietary patterns on cancer prevention and found that AYAs who had access to healthy diets, such as fruits and vegetables from farmers’ markets, were more likely to adopt a healthy lifestyle compared to those who had easy access to junk foods.[26] Evidence now supports the idea that adopting a lifestyle that involves following a diet rich in fruits, vegetables, and whole grains when minimizing the consumption of meat (primarily chicken or cold-water fish) can decrease the risk of developing cancer.[27]

Transcriptomic analysis showed that AYAs, with their unique biology, are known to have excessive immune infiltration and a proliferative nature in ER alpha negative positive (ER+)/HER2 negative (−) breast cancers, which could be influenced by factors like diet and exercise.[28] Dietary choices are a significant component in the risk of breast cancer, along with genetic predisposition, hormonal influences, and environmental exposures.[29] Products that are produced by combining different ingredients and subjecting them to various industrial processes for commercial purposes are termed ultra-processed foods (UPFs) based on the NOVA classification, which includes breakfast cereals, sweet and savory snacks, preprepared frozen dishes, reconstituted meat products, soft and/or sweetened beverages, distilled alcoholic beverages, and additives.[30] A cross-sectional study on non-Hispanic Black, Mexican American, non-Hispanic White AYA population in the US showed an increase in consumption of UPFs from 61.4% to 67.0% from 1999 to 2018.[31] Dietary exposure to these trends in Western diet in AYAs has been shown to increase the risk of developing Breast cancer.[32]

Several studies indicate that the incidence of breast cancer declines among individuals who adhere to a Mediterranean diet (MedDiet) that is abundant in fruits, vegetables, seafood, and olive oil compared to that of the Western diet.[33] Diets rich in fiber and naturally occurring metabolites like phytoestrogens, particularly abundant in soy, are shown to have protective effects when consumed during puberty.[34] Breast cancer is one of the most common cancer forms among female AYAs.[35] Globally, lifestyle factors, such as diets low in milk and whole grains, are considered prominent risk factors for breast cancer among women.[21] Studies have successfully shown that adopting lifestyle changes may prevent 25%–30% of breast cancer instances, according to recent expert reports, making it important to reduce the disease burden at large.[36]

Dietary Advanced Glycation End Products

Advanced glycation end products (AGEs) are highly reactive metabolites that are formed as a result of spontaneous nonenzymatic reactions between lipids, proteins, or nucleic acids and reducing sugars.[37] Endogenously, they are generated within the human body via an intricate sequence of chemical processes referred[34] to as glycoxidation.[38] All uncooked animal-derived foods naturally contain AGEs; however, cooking methods that involve high heat, such as grilling, broiling, roasting, and frying, drive the formation of AGEs in these foods. In addition, dietary habits characterized by high fat, high sugar, and UPFs contribute to the increased AGE consumption we observe in the Westernized diet.[39] The most commonly measured metabolites are carboxyethyl lysine, methylglyoxal (MGO), and carboxymethyl lysine (CML).[40] The browning of foods during cooking enhances flavor but also carries health risks.[41] Studies now indicate that the US food supply is 73% ultra-processed, leading directly to increased consumption. Together with the use of high-heat cooking methods, the modern diet now results in the consumption of high levels of AGEs, with large cohort studies estimating the range of daily intake from <1000 kU/day to >40,000 kU/day.[42–44] The consumption of UPF has also risen among US youths and has contributed to the rise in chronic diseases in this population.[31] There is growing epidemiological evidence that links UPF consumption with poor cardiometabolic health. This serves as a critical example for considering AGEs as a comprehensive biomarker of diet quality in the current era of processed foods.[45]

Dietary Advanced Glycation End Products and Inflammation

The consumption of AGE-rich foods extends beyond their involvement in protein, lipid, and DNA dysfunction. Through activation of the receptor for AGE, AGEs have been implicated in the induction of inflammatory pathways, increased oxidative stress, and the activation of multiple cellular signaling pathways.[46] These mechanisms can promote the growth and progression of cancer by increasing cell division, suppressing cell death (apoptosis), and promoting metastatic pathways.[47] The inflammatory markers increased in response to long-term consumption of AGEs include interleukin-6 IL-6, IL-1a, nuclear factor kappa B, intercellular adhesion molecule-1, and tissue inhibitor of metalloproteinases-1.[48] In fact, chronic or systemic inflammation is a factor in many diseases that have been associated with increased AGE consumption, including obesity, metabolic syndrome, prediabetes, type 2 diabetes, heart disease, Alzheimer’s disease, and, of course, cancer. Foods that induce inflammation, or “inflammatory foods,” include red meat, processed meats, commercial baked goods, refined carbohydrates, deep-fried items, foods high in added sugar, sugar-sweetened beverages, and foods high in saturated fats all have high levels of AGEs. Conversely, anti-inflammatory diets such as the MedDiet are based on foods that are low in AGEs, such as fruits, vegetables, fish, whole grains, olive oil, and nuts. The MedDiet also recommends cooking procedures that can help reduce the production of AGEs.[49] Other inflammatory diets include the Dietary Approaches to Stop Hypertension (DASH) diet, which is similar to the MedDiet but with a greater focus on reducing salt and increasing low-fat dairy products, and the MIND diet, which blends the Mediterranean with the DASH diet. Notably, a recent study showed a negative correlation between AGEs and adherence to the MedDiet in patients from the ILERVAS trial.[49] However, this trial was performed in the older population; no similar studies have been conducted in the AYA population.

Dietary Advanced Glycation End Products and Breast Cancer Risk

The increasing incidence of breast cancer among young women globally is alarming. Recently, an article in the Lancet reviewed the magnitude of cancer burden attributable to modifiable lifestyle factors and found that a high body mass index (BMI) was one of the top three global risk factors for risk-attributable cancer deaths and DALYs in 2019.[21] Hence, it is crucial to understand the association between lifestyle factors, specifically dietary factors, and the susceptibility to breast cancer in the AYA population. There have been many clinical trials evaluating various interventions associated with diet and/or weight loss in breast cancer patients[40] with conflicting results. However, several retrospective analyses of large cohorts have demonstrated the relationship between dietary AGE consumption and breast cancer risk and outcomes in women. They have also been reviewed in detail elsewhere,[40] but to summarize, the study by Omofuma et al.[43] used the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial cohort to investigate the relationship between dietary AGEs and the risk of breast cancer. The study included women between the ages of 55 and 74 years and found that a greater intake of CML-AGE was associated with an increased risk of breast cancer among all women, particularly non-Hispanic White women, those with in situ cancer, and those with hormone receptor-positive breast cancer.

Similarly, the study by Peterson et al.[50] used the AARP cohort to investigate the association between the consumption of dietary AGEs and the incidence of postmenopausal breast cancer in a group of 183,548 women aged between 50 and 71 years. This study also found that increased consumption of dietary AGEs was linked to a higher risk of breast cancer, particularly invasive breast cancer. This association remained even after accounting for other risk factors and dietary habits. The study by Peterson et al.[50] explored the impact of dietary AGE intake on mortality among postmenopausal women between the ages of 50–79 years diagnosed with invasive breast cancer within the Women’s Health Initiative. This study found that a higher consumption of CML-AGEs postdiagnosis was associated with increased breast cancer mortality when compared to women with a low intake of CML-AGEs postdiagnosis. Of note, women who changed from a high CML-AGE intake prediagnosis to a low CML-AGE intake postdiagnosis had decreased breast cancer mortality compared to women with high CML-AGE postdiagnosis. Although these studies were all conducted in the US, a recent epidemiological hospital-based case-control study in Iran was published that utilized food frequency questionnaires to evaluate food intake and physical activity levels in women. Similar to the US-based studies, this study also found a positive association between the consumption of dietary AGEs and increased susceptibility to breast cancer.[51]

The results support that decreasing the consumption of dietary AGEs either before or after diagnosis can improve survival outcomes and highlight the need for additional intervention studies aimed at reducing dietary AGE consumption in breast cancer patients.[44] Furthermore, these studies argue that early dietary (AGE) intervention could reduce the risk of breast cancer in women and stress the need for dietary education early in life and more research into the mechanisms of dietary AGEs in cancer progression. We also posit that future studies should be inclusive of younger women that are representative of the AYA population and/or prospective studies inclusive of this new high-risk group. These data also support the notion that AGEs may represent a more powerful prognostic indicator in these types of studies than either BMI or weight loss.

Mechanistic Insights from Preclinical Models of Mammary Gland Development

The mammary gland is one of the few organs that develops postnatally and, as such, is susceptible to influence by external stimuli, including dietary factors.[34] The gland develops through various stages, including a period of intense proliferation and differentiation during puberty. To assess the impact of dietary AGE consumption during this window of susceptibility, a dietary-AGE mouse model was established to mimic human AGE consumption. Mice were fed for a period of 4 weeks from weaning, and normal mammary development was assessed. Disruption of normal development was observed with increased side branching and a delay in ductal extension through the fat pad. Terminal end buds, an essential and dynamic structure required for normal gland development, were disorganized, hyperproliferative, and larger in size and number. When mice were fed to adulthood (3–12 weeks), hyperproliferative preneoplastic ductal lesions were observed with increased stromal recruitment and activation.[52] Of note, mice fed the high AGE diet during puberty (3–7 weeks) had a more significant number of hyperproliferative preneoplastic lesions in adulthood than those mice fed toward the end of pubertal development (7–12 weeks). As the lifetime risk of breast cancer is established during puberty, these data suggest the importance of intervention strategies, potentially through education for younger women, to help reduce risk during this important time of a woman’s life.

A recent study in the Journal ‘Cell’ found that the glycolytic metabolite methylglyoxal (MGO), an AGE precursor, can deplete BRCA2 protein expression in several human breast cancer cells, inducing haploinsufficiency and subsequent increase in mutational signatures that are linked to breast cancer progression. They speculate that this “…may be an unrecognized yet widespread mechanism that connects environmental or cell-autonomous metabolic alterations with cancer initiation….”[53] Of note, the role of paternal influence should not be ignored, as preclinical studies have shown that paternal diet and environmental factors may contribute to transgenerational breast cancer risk transmission via epigenetic changes in their daughters.[54]

Clinical Implications to Young Women’s Breast Cancer

Further investigation is needed to determine the impact of consuming high levels of AGE-rich foods on breast cancer risk in young women. Epidemiological studies on this population, as well as experimental research to elucidate the underlying processes, are critical for developing preventative interventions targeted to the specific requirements of young women at risk of breast cancer. Education and awareness among AYAs diagnosed with breast cancer should be given utmost importance. They should take advantage of the current technological advances,[55] for example, the study piloting the “Young, Empowered and Strong” interactive web-based intervention portal, which was created to advocate self-monitoring in women with breast cancer. In addition, it can support the management of symptoms and concerns in these women.[56] Using this platform, the group went on to show that AYAs diagnosed with metastatic breast cancer, who can have higher physical and psychosocial burdens than older women diagnosed with breast cancer, included concerns about diet (54.1%) and exercise (61.6%). Indeed, emerging evidence supports that engaging in 45–60 min of daily exercise can result in significant changes in growth factors and hormones associated with cancer, which is potentially very important in younger women.[27] To help women adhere to a healthier lifestyle, the American Cancer Society has published guidelines for both Diet and Physical Activity for cancer prevention. These recommendations are to (1) either engage in 150 min of moderate-intensity or 75 min of high-intensity exercise per week, (2) to maintain a healthy BMI (18.5–24.9 kg/m2), and (3) to limit alcohol intake to no more than one drink per day.[57] This insight reinforces that increasing education and awareness surrounding modifiable lifestyle factors in younger populations can serve as an intervention to reduce risk. Assessing dietary patterns, creating personalized nutrition regimens based on individual metabolic and genetic characteristics, and performing randomized controlled trials to evaluate the BMI effectiveness of these treatments in preventing cancer growth and improving patient outcomes could be one of the most effective strategies in AYAs.[58]

In fact, studies involving mother-daughter dyads have revealed the significance of family-based approaches to breast cancer prevention. They found that engaging teenage girls in physical exercise and leading a healthy lifestyle significantly lowered their chance of developing breast cancer, even if they had a family history of the condition. This emphasizes that preventive efforts should begin early in life and emphasize modifiable risk factors, including diet and exercise, to build lifetime health practices and minimize breast cancer risk.[59]

Footnotes

Conflicts of interest

VJF is on the board of the not-for-profit anti-AGEs Foundation and has no other conflict of interest to declare. All other authors do not have any conflict of interest to declare.

Data availability statement

Further details of the data referred to and discussed in the manuscript are available from the corresponding author upon request.

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Data Availability Statement

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