Abstract PS14-17: Rapamycin inhibits stem cell function and diminishes inflammation and senescence markers in human mammary gland

Abstract

Abstract Gene expression profiles of some subtypes of breast cancer were shown to correspond to the profiles of the basal or luminal mammary stem/progenitor cell-enriched epithelial cells implicating the mammary stem cells (MaSCs) as tumor-initiating cells for certain types of breast cancer. Moreover, there is growing evidence that MaSCs may initiate neoplastic transformation when dysregulated in mouse models. We have previously reported an increased frequency of the MaSC-enriched Lin-/CD49fhigh/CD24+ basal cells in old mice (>27 month) compared to young ones (2-4 month) along with an increase of hyperplasic lesions. Gene expression profile revealed an increase of immune and inflammatory responses in old basal cells and stroma cells indicating that aging-induced immune and inflammatory responses might initiate basal cell expansion and transformation. Our preliminary data on mice using rapamycin, an immune and inflammation inhibitor, were very encouraging so we decided to start a clinical window trial (NCT02642094) to test whether rapamycin could reduce biomarkers associated with progression to invasive breast cancer and MaSC numbers in postmenopausal patients with atypical ductal hyperplasia (ADH) or ductal carcinoma in situ (DCIS). The patients enrolled in the trial took rapamycin (sirolimus, 2mg/day) for 5-7 days with 3-7 days of washout before surgery. The adjacent non-tumor surgical tissues were used for the measurements of sphere formation efficiency (SFE) of the basal and luminal cells. The control group were patients with ADH/DCIS who did not take the drug. Rapamycin treatment significantly diminished the SFE of the basal MaSC. Immunohistochemical staining of the biopsies and surgical tissues showed that rapamycin treatment significantly decreased the levels of COX2 (an inflammation marker) and p16 (a senescence marker), and moderately increased p62 (an autophagy marker). Furthermore, rapamycin significantly reduced the proliferation marker Ki67 staining. In conclusion, rapamycin inhibits MaSCs function and senescence and inflammation features in human mammary glands. Whether the suppression of the senescence-associated inflammatory responses is the mechanism by which rapamycin suppresses MaSC function is under investigation. Citation Format: Hakim Bouamar, Larry Broome, Xiang Gu, Alia Nazarullah, Andrew Brenner, Virginia Kaklamani, Ismail Jatoi, Lu-Zhe Sun. Rapamycin inhibits stem cell function and diminishes inflammation and senescence markers in human mammary gland [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS14-17.