The Surge of Breast Cancer in Young Women: Is Mitochondrial Dysfunction the Hidden Culprit?

The common belief that breast cancer primarily affects older adults may not always be very informative, especially regarding young women under 40 yeard, as such cases frequently present with earlier onset and more severe outcomes.[1] In recent years, the early onset of breast cancer in young women (BCYW) has increasingly alarmed healthcare professionals, researchers, and young adults. In 2022, women under 39 accounted for approximately 10.71% of the 2,295,720 breast cancer cases worldwide. Nearly half (47.5%) of BCYW cases occur in the 20–34 years’ age group,[2] which is below the recommended age for mammography screening. The World Health Organization (WHO) predicts that BCYW cases will continue to rise until 2050, potentially reaching 278.6 thousand cases.[2] The WHO data indicate that the average age of the diagnosis is expected to be between 33 and 34 in 2040. This suggests that individuals likely to be diagnosed in 2040 are approximately 17–18 years old today,[2,3] highlighting the need for new knowledge and advancements to mitigate future breast cancer risks and vigorously pursue logical, unexplored leads. The causes of this trend and the increasing incidence among young women are not well understood, and the issue of causative factors and cellular switches leading to BCYW remains elusive.[3-6] Since a large majority of breast cancer cases (sporadic breast cancer) are not associated with predisposed cancer genes or family history, the rising incidence of BCYW worldwide is thought to be influenced by various external and internal factors and their interactions within the context of mammary gland biology, including exposure to modifiable risk factors, lifestyle choices, and more.[3-5] While a substantial body of recent research has revealed the differential expression and functions of molecules and cancer hallmark pathways at various identifiable stages of breast cancer progression,[7] the field is still far from achieving predictive biomarkers or tests that could help monitor which young adults might be at risk, similar to other chronic diseases. This is partly due to the complex nature of mammary gland biology, which is greatly influenced by interactions among different cell types in breast tissues, local and secreted hormones or metabolites, feedback mechanisms, and the cyclical aspects of ovarian and endometrial biology.[1,5] As most breast cancers take several years to become clinically detectable, the changing biology of the mammary gland, influenced by extrinsic and intrinsic factors from puberty to adolescence, is thought to profoundly affect the development of BCYW.[4,5] Recently, it has been proposed that the early onset of breast cancer may relate more to accelerated biological aging than to chronological aging.[8] However, this hypothesis raises new testable hypotheses, including what triggers accelerated biological aging in targeted mammary gland cells, whether it results from the convergence of cancer hallmarks or the other way around, and the functional sufficiency of accelerated biological aging for developing BCYW, among many other pertinent questions. In this context, extensive research has established a strong connection between aging and cancer through shared biological markers known as the hallmarks of aging and the hallmarks of cancer.[9-13] A pivotal player and common hallmark in both processes is mitochondrial dysfunction – a condition in which mitochondria, the energy-producing organelles within cells, lose their efficiency and integrity.[10,14] While mitochondria are recognized as the source of cellular energy, they also serve as regulatory hubs having modifying effects on a number of cellular processes involved in the development of cancer,[15] including cell death, signaling, epigenetic pathways, and metabolism. Mitochondrial dysfunction can also create a microenvironment that supports cancer growth and works in tandem with the hallmarks of cancer.[16] Studies in breast cancer research suggested the proposed connection. Accelerated biological aging has been observed in breast cancer survivors and in the normal breast tissue of women with cancer, including those with BRCA mutations[17-20] as well as in the sebaceous gland.[21] There is also a potential link between mitochondrial DNA (mtDNA) depletion, mitochondrial health as well as cancer risk, and recurrence.[18,22,23] Mitochondria have their own genome, distinct from nuclear DNA, making them unique among cellular components. Defects in mtDNA replication and repair mechanisms lead to changes in energy metabolism, oxidative stress, and epigenetic components, all with an established role in breast cancer development. Throughout puberty and the later stages of breast development into adolescence, the breasts experience continual remodeling driven by hormonal signals, biological interactions, and various factors.[1,5] During this time, breast cells become increasingly vulnerable to both internal factors (such as inflammation and oxidative damage) and external influences (including lifestyle choices, environmental factors, and carcinogens). These factors can alter the functioning of different cell types in the breasts, influencing the biological determinants of breast cancer characteristics. Mitochondrial dysfunction, a key driver of biological aging, can be triggered by various external factors that damage the cells and impair mitochondrial function. Environmental toxins such as air pollutants (e.g., heavy metals and pesticides) and consumer chemicals (e.g., phthalates, etc.) contribute to oxidative stress and inflammation, damaging mitochondria. In addition, lifestyle choices such as diet-containing high AGEs, smoking, and alcohol use further add to the mitochondrial damage by increasing reactive oxygen species and disrupting mitochondrial processes. Mitochondria rely on a quality control system – mitophagy and biogenesis – to maintain function, but environmental and lifestyle stressors can hinder this system and accelerate age-related decline.[1] Epigenetic alterations, shaped by both external and internal factors, can further impair mitochondrial health. Therefore, these external and internal factors may negatively affect mitochondrial membrane potential, alter its structure, and initiate inflammation, which can ultimately compromise energy metabolism and cellular health. Recognizing these triggers is essential for preventing mitochondrial harm associated with breast disease. Considering these insights, exploring a noninvasive method to monitor mitochondrial health could act as a biomarker for assessing the risk of developing BCYW. Moreover, it is essential to define the types of upstream modifiers and external risk factors affecting mitochondrial health from the outset. Here, we propose that mitochondrial dysfunction – a shared hallmark of cancer and aging – might be the core mechanism at the interface of external risk factors, intrinsic factors, and hallmarks of breast cancer development. Hormonal changes during puberty through adolescence heighten susceptibility to both external and internal breast cancer risk factors, many of which could contribute to mitochondrial dysregulation. We further hypothesize that therapies aimed at preserving mitochondrial function or delaying mitochondrial aging may serve as preventive strategies for early-onset cancers in women across all age groups. In conclusion, mitochondria are not just passive energy suppliers; they are active regulators of cancer development and progression. Understanding mitochondrial dysfunction and its relationship with cancer hallmarks could be crucial for addressing the early onset of breast cancer. Data availability statement Further details of data referred to and discussed in the manuscript are available from the corresponding author upon request.