The objective of this project is to understand the role of the mechanistic Target of Rapamycin (mTOR) pathway in the association between energy imbalance and prognosis in patients with breast cancer and the potential benefits of targeting mTOR to inhibit its activation to improve clinical outcomes in these patients. Energy imbalance is an important factor affecting breast cancer prognosis. Although behavioral interventions leading to weight reduction have shown a potential to reduce breast cancer recurrence and mortality rates, the biological mechanisms between obesity and breast cancer outcomes are not entirely clear. It is crucial to identify mechanisms through which overall and central adiposity exert their effects. Lifestyle interventions may not be applicable or effective for all women with breast cancer; targeting the underlying biological mechanisms may open new opportunities to improve the prognosis for a greater number of patients. We propose that mTOR pathway signaling in breast tumors is a significant and targetable mechanism mediating energy imbalance and breast cancer prognosis. Our preliminary data show a positive linear association of body mass index and waist circumference with mTOR pathway activation, as indicated by phosphorylated mTOR (p- mTOR) expression levels, in patients with breast cancer overall and in estrogen receptor-negative (ER-) tumors. Also, from the expression of several phospho-proteins, higher vs. lower levels of mTOR pathway activities are associated with disease-free survival. The main weaknesses of these data are the lack of information on treatment, and the number of patients in subtypes is small. We will address these research gaps in our proposed Pathways Study, a prospective cohort study of 4,505 women who had received a diagnosis of incident primary invasive breast cancer. In this cohort, we have documented 571 recurrences, 420 second primary cancers, and 880 deaths with data on ER status. We will assess mTOR pathway activities using a 10-marker immunohistochemistry panel in tumor tissue samples. We will evaluate the association between body size (BMI, waist circumference, and waist-to-hip ratio) and mTOR pathway activation in breast tumors (Aim 1) and assess the association of mTOR pathway activation independently and jointly with body size on breast cancer outcomes (Aim 2). To further understand the role of the mTOR pathway in prevention, we will examine whether the status of non-obesity, exercise, and metformin use, as interventions of energy imbalance, affects patient outcomes through mTOR pathway regulation (Aim 3). Our proposal is innovative in employing a large panel of phospho-protein expression, comprehensive clinical and epidemiologic data, and adequate statistical power for ER- breast cancer subtype. The results will improve our understanding of the extent to which mTOR pathway activation, which is modifiable in early-stage breast cancer, may alleviate the influence of energy imbalance on breast cancer prognosis and shed light on the potential for promoting energy balance and using mTOR inhibitors as a combination strategy to improve clinical outcomes.
Nearly half (46%) of US women diagnosed with breast cancer are overweight or obese and at an elevated risk for poor prognosis. The proposed research will improve the understanding of how energy imbalance affects breast cancer outcomes and the role of mTOR pathway activation as a targetable mediator in breast tumors, which will ultimately reveal novel strategies for improving clinical outcomes. The proposed research is in line with the part of NIH?s mission of developing fundamental knowledge that will contribute to reducing the burden of breast cancer.
