mTOR inhibition abrogates human mammary stem cells and early breast cancer progression markers

Breast Cancer Research

Research

Lu-Zhe Sun¹  Hakim Bouamar¹  Larry Esteban Broome¹  Andrew Jacob Brenner²  Michael Garcia²  Kate Ida Lathrop²  Virginia Kaklamani²  Alia Nazarullah³  Yidong Chen⁴  Ismail Jatoi⁵  Karla Moncada Gorena⁶ 

[1] Department of Cell Systems and Anatomy, School of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA;Department of Medicine, School of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA;Department of Pathology, School of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA;Department of Population Health Sciences, School of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA;Greheey Children’s Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA;Department of Surgery, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA;Flow Cytometry Core Facility, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA;

关键词: Stem cells;    mTOR;    Rapamycin;    Sirolimus;    Progression markers;    Mammary stem cells;   

DOI  :  10.1186/s13058-023-01727-z

 received in 2023-07-10, accepted in 2023-10-04,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundMammary physiology is distinguished in containing adult stem/progenitor cells that are actively amending the breast tissue throughout the reproductive lifespan of women. Despite their importance in both mammary gland development, physiological maintenance, and reproduction, the exact role of mammary stem/progenitor cells in mammary tumorigenesis has not been fully elucidated in humans or animal models. The implications of modulating adult stem/progenitor cells in women could lead to a better understanding of not only their function, but also toward possible breast cancer prevention led us to evaluate the efficacy of rapamycin in reducing mammary stem/progenitor cell activity and malignant progression markers.MethodsWe analyzed a large number of human breast tissues for their basal and luminal cell composition with flow cytometry and their stem and progenitor cell function with sphere formation assay with respect to age and menopausal status in connection with a clinical study (NCT02642094) involving a low-dose (2 mg/day) and short-term (5–7 days) treatment of the mTOR inhibitor sirolimus. The expression of biomarkers in biopsies and surgical breast samples were measured with quantitative analysis of immunohistochemistry.ResultsSirolimus treatment significantly abrogated mammary stem cell activity, particularly in postmenopausal patients. It did not affect the frequency of luminal progenitors but decreased their self-renewal capacity. While sirolimus had no effect on basal cell population, it decreased luminal cell population, particularly in postmenopausal patients. It also significantly diminished prognostic biomarkers associated with breast cancer progression from ductal carcinoma in situ to invasive breast cancer including p16INK4A, COX-2, and Ki67, as well as markers of the senescence-associated secretary phenotype, thereby possibly functioning in preventing early breast cancer progression.ConclusionOverall, these findings indicate a link from mTOR signaling to mammary stem and progenitor cell activity and cancer progression.Trial registration This study involves a clinical trial registered under the ClinicalTrials.gov identifier NCT02642094 registered December 30, 2015.

【 授权许可】

CC BY   
© The Author(s) 2023

【 图 表 】

Fig. 3

13690_2023_1196_Figb_HTML.png

12951_2017_270_Article_IEq9.gif

12951_2017_270_Article_IEq8.gif

Fig. 1

12951_2015_111_Article_IEq1.gif

Fig. 2

Fig. 2

Fig. 3

Fig. 4