Principal Investigator

Luzhe
Sun
Awardee Organization

University Of Texas Hlth Science Center
United States

Fiscal Year
2019
Activity Code
R01
Project End Date

Aging mammary stem cells and breast cancer prevention

Our long-term goal is to determine how the aging-related breast cancer can be specifically prevented. This is an unanswered question largely because the cellular and molecular mechanisms underlying the aging-related increase in breast cancer incidence are poorly understood. We recently found that the percentage of mammary stem cells (MaSCs) in mouse mammary gland increases steadily with age. More significantly, both old (22-30 months) mammary glands and old MaSC-regenerated mammary glands obtained by in vivo transplantation showed significantly more foci of hyperplasia, atypical ductal hyperplasia (ADH), and ductal carcinoma in situ (DCIS) than young (4-6 months) mammary glands and young MaSC-regenerated mammary glands respectively. This is the first experimental demonstration that MaSCs are the precursors of spontaneous neoplastic lesions and aging predisposes MaSCs to neoplastic transformation. Whole genome RNA sequencing and gene ontology analysis revealed a significantly elevated senescence-associated inflammatory response (SIR) in aging mammary stromal cells and significantly elevated immune and inflammatory responses in aging MaSCs, which likely engendered the transforming property of MaSCs. Indeed, treatment with the anti-inflammatory/immune modulatory drug rapamycin for 5-10 days not only reverted the phenotypes of the old mammary glands and old MaSCs similar to those of young mammary glands and young MaSCs, respectively, but also resulted in the loss of the transforming property of the old MaSCs. Our most recent preliminary data show that aging is associated with increased levels of autophagy markers in old mammary glands, which were not further increased by rapamycin treatment suggesting that excessive autophagy in the presence of rapamycin might have caused hyperplastic and dysplastic cells in the old mammary gland to undergo apoptosis and/or autophagic cell death instead of cell survival and tumor progression. These novel observations led us to hypothesize that aging-associated mammary tumorigenesis may be due to the generation of aberrant MaSCs capable of forming neoplastic lesions and can be prevented through pharmacological interventions. We will test the hypothesis with three specific aims. Although rapamycin is known to inhibit breast cancer progression, whether short-term treatment with rapamycin can prevent mammary tumorigenesis via a MaSC mechanism is not known. Thus, in Aim 1, we propose to determine an effective dosage of short-term rapamycin treatment in abrogating the transforming phenotype of old MaSCs. We will also determine the efficacy of an mTOR kinase inhibitor in preventing old MaSC-mediated neoplastic lesion formation in mice. In Aim 2, we will investigate whether rapamycin exacerbates autophagy to cause autophagic cell death or apoptosis of human and mouse DCIS cells and attenuates immune and inflammatory responses in old MaSCs to abrogate their transforming activity. We will also investigate other age-related cellular pathways and processes regulated by rapamycin, which may cause the dysfunction of MaSC during aging. In Aim 3, we will carry out clinical studies to determine the effect of aging on human mammary stem/progenitor cell function and the efficacy of short-term rapamycin treatment in mitigating biomarkers associated with breast cancer recurrence in patients with DCIS. Completion of the proposed aims will fill knowledge gap and make a breakthrough in our understanding of the cellular and molecular mechanisms that mediate neoplastic transformation by MaSCs during progressive aging. It will also establish a foundation for future clinical studies of interventional treatment and/or non-treatment trials in preventing aging-related breast cancer, which should particularly benefit the population at high risk for breast cancer.

Publications

  • Chen G, Bouamar H, Sun LZ. Isolation, Culture, and Differentiation of Mammary Epithelial Stem/Progenitor Cells from Fresh or Ex Vivo Cultured Human Breast Tissue. Current protocols in cell biology. 2019 Mar;82(1):e65. Epub 2018 Sep 28. PMID: 30265440
  • Gu X, Wang B, Zhu H, Zhou Y, Horning AM, Huang TH, Chen Y, Houghton P, Lai Z, Michalek JE, Sun LZ. Age-associated genes in human mammary gland drive human breast cancer progression. Breast cancer research : BCR. 2020 Jun 15;22(1):64. PMID: 32539762
  • Dong Q, Gao H, Shi Y, Zhang F, Gu X, Wu A, Wang D, Chen Y, Bandyopadhyay A, Yeh IT, Daniel BJ, Chen Y, Zou Y, Rebel VL, Walter CA, Lu J, Huang C, Sun LZ. Aging is associated with an expansion of CD49fhi mammary stem cells that show a decline in function and increased transformation potential. Aging. 2016 Nov 15;8(11):2754-2776. PMID: 27852980
  • Chen G, Ding XF, Pressley K, Bouamar H, Wang B, Zheng G, Broome LE, Nazarullah A, Brenner AJ, Kaklamani V, Jatoi I, Sun LZ. Everolimus Inhibits the Progression of Ductal Carcinoma In Situ to Invasive Breast Cancer Via Downregulation of MMP9 Expression. Clinical cancer research : an official journal of the American Association for Cancer Research. 2020 Mar 15;26(6):1486-1496. Epub 2019 Dec 23. PMID: 31871301
  • Chen G, Ding XF, Bouamar H, Pressley K, Sun LZ. Everolimus induces G1 cell cycle arrest through autophagy-mediated protein degradation of cyclin D1 in breast cancer cells. American journal of physiology. Cell physiology. 2019 Aug 1;317(2):C244-C252. Epub 2019 May 22. PMID: 31116586
  • Liu Z, Wang L, Yang J, Bandyopadhyay A, Kaklamani V, Wang S, Sun LZ. Estrogen receptor alpha inhibits senescence-like phenotype and facilitates transformation induced by oncogenic ras in human mammary epithelial cells. Oncotarget. 2016 Jun 28;7(26):39097-39107. PMID: 27259243
  • Bouamar H, Broome LE, Lathrop KI, Jatoi I, Brenner AJ, Nazarullah A, Gorena KM, Garcia M, Chen Y, Kaklamani V, Sun LZ. mTOR inhibition abrogates human mammary stem cells and early breast cancer progression markers. Breast cancer research : BCR. 2023 Oct 30;25(1):131. PMID: 37904250

Clinical Trials

Study Name Clinical Trial ID
Aging Mammary Stem Cells and Breast Cancer Prevention NCT02642094