Abstract
Breast cancer cells with stem-like properties are critical for tumor progression, yet much about these cells remains unknown. Here, we characterize a population of stem-like breast cancer cells expressing the integrin αvβ3 as transcriptionally related to activated stem/basal cells in the normal human mammary gland. An unbiased functional screen of genes unique to these cells identified the matrix protein TGFBI (BIG-H3) and the transcription factor ZEB1 as necessary for tumorsphere formation. Surprisingly, these genes were not required for cell proliferation or survival, but instead maintained chromosomal stability. Consistent with this finding, CRISPR deletion of either gene synergized with PARP inhibition to deplete αvβ3+ stem-like cells, which are normally resistant to this therapy. Our findings highlight a critical role for TGFBI-ZEB1 protection against genetic stress as a key attribute of activated stem-like cells and suggest that disrupting this ability may enhance their “BRCAness” by increasing sensitivity to PARP inhibitors.
Highlights
Tumor-initiating cancer stem cells (CSCs) bearing similarities to adult mammary stem cells (MaSCs) are important contributors to breast cancer progression and metastasis[1,2,3,4]
We show that adding recombinant human TGFBI protein is sufficient to drive ZEB1 protein expression in control and TGFBI knockout cells (Fig. 5c) and rescue defective tumorsphere formation caused by TGFBI deletion (Fig. 5d)
By comparing our whole transcriptome sequencing data from sorted αvβ3+ CSCs with published gene sets enriched in stem/basal cells during the luteal (Active) and follicular (Inactive) phases of the menstrual cycle, we show a striking correlation between αvβ3+ CSCs and activated stem/basal cells from the normal human mammary gland
Summary
Tumor-initiating cancer stem cells (CSCs) bearing similarities to adult mammary stem cells (MaSCs) are important contributors to breast cancer progression and metastasis[1,2,3,4]. The mammary gland is one of the most dynamic organs in adult women, undergoing robust epithelial remodeling in response to hormones during the menstrual cycle and pregnancy that is driven by stem cells. MaSCs respond to hormones indirectly via paracrine signals to become active and contribute to epithelial remodeling[5,6,7,8] since they lack hormone receptors[9]. These active stem cells exhibit enhanced proliferation and migration[5,6,7,8], features that make this signaling state likely to be hijacked by tumor cells. Our prior findings provided valuable insight regarding the aggressive nature of αvβ3+ CSCs and emphasized the need to further elucidate the unique genes and signaling pathways required for their function
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
