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Grant Details

Grant Number: 5R37CA248371-05 Interpret this number
Primary Investigator: Cheng, Ting-Yuan
Organization: Ohio State University
Project Title: Energy Balance, Mtor Pathway Signaling, and Breast Cancer Prognosis
Fiscal Year: 2024


Abstract

Project Summary/Abstract 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.



Publications

The HealthStreet Cancer Survivor Cohort: a Community Registry for Cancer Research.
Authors: Cheng T.D. , Chaudhari P.V. , Bitsie K.R. , Striley C.W. , Varma D.S. , Cottler L.B. .
Source: Journal of cancer survivorship : research and practice, 2024 Apr; 18(2), p. 366-374.
EPub date: 2022-01-28.
PMID: 35089522
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mTOR pathway candidate genes and energy intake interaction on breast cancer risk in Black women from the Women's Circle of Health Study.
Authors: Ilozumba M.N. , Yaghjyan L. , Datta S. , Zhao J. , Hong C.C. , Lunetta K.L. , Zirpoli G. , Bandera E.V. , Palmer J.R. , Yao S. , et al. .
Source: European journal of nutrition, 2023 Sep; 62(6), p. 2593-2604.
EPub date: 2023-05-20.
PMID: 37209192
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mTOR pathway candidate genes and physical activity interaction on breast cancer risk in black women from the women's circle of health study.
Authors: Ilozumba M.N. , Yaghjyan L. , Datta S. , Zhao J. , Gong Z. , Hong C.C. , Lunetta K.L. , Zirpoli G. , Bandera E.V. , Palmer J.R. , et al. .
Source: Breast cancer research and treatment, 2023 May; 199(1), p. 137-146.
EPub date: 2023-03-08.
PMID: 36882608
Related Citations

mTOR pathway candidate genes and obesity interaction on breast cancer risk in black women from the Women's Circle of Health Study.
Authors: Ilozumba M.N. , Yaghjyan L. , Datta S. , Zhao J. , Hong C.C. , Lunetta K.L. , Zirpoli G. , Bandera E.V. , Palmer J.R. , Yao S. , et al. .
Source: Cancer causes & control : CCC, 2023 May; 34(5), p. 431-447.
EPub date: 2023-02-15.
PMID: 36790512
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Trends in Dietary Vitamin A Intake Among US Adults by Race and Ethnicity, 2003-2018.
Authors: Cheng T.D. , Ferderber C. , Kinder B. , Wei Y.J. .
Source: JAMA, 2023-03-28; 329(12), p. 1026-1029.
PMID: 36976287
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Association Between Recreational Physical Activity and mTOR Signaling Pathway Protein Expression in Breast Tumor Tissue.
Authors: Cheng T.D. , Zhang R. , Gong Z. , Qin B. , Cannioto R.A. , Datta S. , Zhang W. , Omilian A.R. , Yao S. , Khoury T. , et al. .
Source: Cancer research communications, 2023 Mar; 3(3), p. 395-403.
EPub date: 2023-03-07.
PMID: 36895729
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Low muscle mass is associated with a higher risk of all-cause and cardiovascular disease-specific mortality in cancer survivors.
Authors: Zhang D. , Spiropoulos K.A. , Wijayabahu A. , Christou D.D. , Karanth S.D. , Anton S.D. , Leeuwenburgh C. , Liang M. , Wheeler M. , Yang D. , et al. .
Source: Nutrition (Burbank, Los Angeles County, Calif.), 2023 Mar; 107, p. 111934.
EPub date: 2022-12-10.
PMID: 36563433
Related Citations

Associations of Total Body Fat Mass and Skeletal Muscle Index with All-Cause and Cancer-Specific Mortality in Cancer Survivors.
Authors: Aduse-Poku L. , Karanth S.D. , Wheeler M. , Yang D. , Washington C. , Hong Y.R. , Manini T.M. , Fabregas J.C. , Cheng T.D. , Braithwaite D. .
Source: Cancers, 2023-02-08; 15(4), .
EPub date: 2023-02-08.
PMID: 36831420
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Intraindividual Reliability of Opportunistic Computed Tomography-Assessed Adiposity and Skeletal Muscle Among Breast Cancer Patients.
Authors: Aduse-Poku L. , Gopireddy D.R. , Hernandez M. , Lall C. , Divaker J. , Falzarano S.M. , Masood S. , Datta S. , Zhang W. , Jo A. , et al. .
Source: JNCI cancer spectrum, 2022-11-01; 6(6), .
PMID: 36222575
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mTOR pathway gene expression in association with race and clinicopathological characteristics in Black and White breast cancer patients.
Authors: Ilozumba M.N. , Yao S. , Llanos A.A.M. , Omilian A.R. , Zhang W. , Datta S. , Hong C.C. , Davis W. , Khoury T. , Bandera E.V. , et al. .
Source: Discover oncology, 2022-05-24; 13(1), p. 34.
EPub date: 2022-05-24.
PMID: 35608730
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Associations of Computed Tomography Image-Assessed Adiposity and Skeletal Muscles with Triple-Negative Breast Cancer.
Authors: Aduse-Poku L. , Bian J. , Gopireddy D.R. , Hernandez M. , Lall C. , Falzarano S.M. , Masood S. , Jo A. , Cheng T.D. .
Source: Cancers, 2022-04-06; 14(7), .
EPub date: 2022-04-06.
PMID: 35406618
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Body fatness and breast cancer risk in relation to phosphorylated mTOR expression in a sample of predominately Black women.
Authors: Cheng T.D. , Omilian A.R. , Yao S. , Zhang W. , Datta S. , Bshara W. , Ondracek R.P. , Davis W. , Liu S. , Hong C.C. , et al. .
Source: Breast cancer research : BCR, 2021-07-30; 23(1), p. 77.
EPub date: 2021-07-30.
PMID: 34330319
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