The majority of breast cancer cases are estrogen receptor (ER?)-positive. While hormonal therapyimproves clinical outcomes for about half of patients with ER?-positive breast cancer, de novo or acquiredresistance represents a significant clinical challenge. Among several underlying mechanisms, hot-spot pointmutants of ER? are known to confer therapeutic resistance due to their estrogen-independent transcriptionalactivity. Thus, mitigating aberrant transcription activity of these ER? mutants holds promise for overcomingtherapeutic resistance in treatment of ER?-positive breast cancer.

The mTORC1 pathway regulates multiple cellular processes to promote a switch from catabolic toanabolic metabolism and is thus under tight regulatory control by growth factor signaling and nutrientsensing pathways. Dysregulation of this complex machinery is implicated in many cancers, so definingthe key mechanisms by which mTORC1 senses changes in cellular homeostasis to activate growthsignals is of great relevance. Spatial regulation of mTORC1 signaling has been recognized as a majormechanism that influences the cellular response to nutrients and the lysosome is central to thisprocess.

We respond to PQ3 with our data showing that tumor PD-L1 (CD274, B7-H1) is a major regulator of tumorinflammatory infiltrates. Our preliminary data show that melanoma PD-L1 regulates TIL through severalpreviously unknown tumor-intrinsic and extrinsic mechanisms. We define novel effects of tumor intrinsic PD-L1signaling on tumor proliferation, sensitivity to immune killing, in vivo growth independent of anti-tumorimmunity, and regulation of mTOR signals.

Estrogen receptor (ER)? exhibits an antitumor activity in multiple cancer types in both tumor-intrinsicand -extrinsic manners. However, little is known as to how such activity can be harnessed with high efficacyand precision, nor is it clear which host cell type(s) mediates the tumor-extrinsic function of ER?. These majorknowledge gaps hamper efforts to unleash ER? antitumor activity for cancer therapies. We recently discovereda phosphotyrosine-dependent signaling axis that controls ER? antitumor activity.

As of 2014, there are approximately 14.5 million cancer survivors within the United States and this populationis projected to grow to 19 million by 2024. Cancer survivors exhibit an accelerated aging phenotype that ishypothesized to be a result of their exposure to chemotherapy. Despite the preponderance of evidencesuggesting that this accelerated aging phenotype happens, there are few basic science initiatives poised tostudy the underlying molecular mechanisms and their therapeutic implications.