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.
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