Regulation of Luminal Stem Cell Function and Basal-like Breast Cancer Initiation by Sox9
Christin, John Robert
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Breast cancer is the most common cancer diagnosed in women and is the second most common cause of cancer death in women. However, not all breast tumors are equally deadly as targeted therapies against ESR1, PGR and ERBB2 have been developed and used effectively against tumors expressing these receptors. Unfortunately, there are 15-20% of breast tumors that do not express ESR1, PGR, or ERBB2 with this subgroup being called triple negative breast cancer (TNBC) and/or basal-like breast cancer (BLBC). These tumors have a worse overall prognosis due to the lack of treatment modalities. While TNBC and BLBC are distinct definitions with the former being defined by the lack of ESR1, PGR, and HER2 protein expression in the tumor and the latter by a transcriptional signature of 50 genes in the tumor, the tumor types they describe overlap resulting in terms that are sometimes used interchangeably. Currently, TNBC/BLBC is thought to arise from the estrogen receptor negative (ESR1- luminal compartment of the mammary epithelial hierarchy as humans with a genetic predisposition to TNBC/BLBC have an expanded ESR1 - luminal compartment. Furthermore, only those mouse tumor models where ESR1- luminal cells are targeted with tumorigenic mutations are capable of recapitulating human disease. With the ESR1- luminal cell of origin in mind, our group recently determined, via lineage tracing, that there is a long-lived ESR1- luminal stem cell, marked by the transcription factor Sox9, that would be capable of accumulating the necessary mutational hits over time. In order to determine whether or not Sox9 plays a functional role in ESR1- luminal cell biology, the work described herein used a combination of in vitro stem cell culture and mouse models to demonstrate that Sox9 is not just a marker of ESR1- luminal stem cells but also required for their normal function and transformation into TNBC/BLBC. Using a conditional Sox9 knockout mouse model we have demonstrated that ESR1- luminal cells lacking Sox9 are completely depleted of stem cell activity ex vivo and display a developmental delay in vivo during pregnancy. To determine how the loss of Sox9 affected ESR1- luminal cells, we then performed transcriptomic analysis of ESB1- luminal cells lacking Sox9 and determined that NF kB signaling pathways, both canonical and non-canonical, were compromised relative to the control. Furthermore, we found that inhibition of either canonical or non-canonical NFkB signaling in ESR1- luminal cells greatly impaired ESR1- luminal stem cell activity. To ascertain Sox9's role in tumor initiation and progression, we conditionally knocked out Sox9 in a model of TNBC/BLBC which resulted in significantly delayed tumor onset relative to the control. Interestingly, all tumors that did arise from the Sox9 conditional knockout animals remained positive for Sox9, demonstrating positive selection for unrecombined ESR1- cells, as it is only these knockout escapees that are capable of transformation. As a whole, our data show that Sox9 is necessary for ESR1- luminal stem cell activity, is responsible for regulating NFkB signaling in ESR1- luminal cells, and is necessary for the initiation and progression of TNBC/BLBC.
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