The tumor suppressor BRCA1 plays an important role in the homologous recombination (HR) pathwayof DNA double strand break (DSB) repair. From a mechanistic perspective, BRCA1 facilitates recruitment ofnucleases required for end resection, the commitment step in HR repair, yet paradoxically, BRCA1 has beenshown to inhibit the nuclease activity in vitro. It is unclear how nuclease-recruiting and -inhibiting activities ofBRCA1 can be reconciled in HR repair.

Most BRCA1-asociated breast tumors are basal-like, yet they originate from luminal progenitor cells.BRCA1 plays important roles in double strand break (DSB) repair and response to DNA replication stress.However, it remains a conundrum as to whether these ubiquitously important functions of BRCA1 are sufficientto account for its cell lineage-specific breast tumor suppression. Filling this longstanding intellectual disconnectcould inform more effective risk assessment and disease prevention.

We are requesting funds to purchase a SARRP image-guided x-ray platform in order to continually support atotal of 26 research projects. Among the currently funded projects that requires the use of the irradiator, nine ofthem are NIH RO1, one PO1 and one U-42 projects. Additionally, one funded FDA approved phase1/2 study andfour NIH RO1 projects that are likely to get funded (currently under council review) proposed to use theirradiator.

Basic Research

The two subtypes of estrogen receptor, ERa and ERb, carry out non-overlapping functions inreproductive biology. ERb is capable of both interfering with ERa function and exerting its biological activityindependent of ERa. It remains unclear how the ERa-independent and ERa-competing functions of ERb areregulated. We recently made the pioneering discovery of an ERb-specific phosphotyrosine switch thatregulates ERb function in reproductive organs.

OverallSystems Analysis of Epigenomic Architecture in Cancer ProgressionDespite anti-hormone therapies in patients, the cognate receptors ER? and AR can remain functional tosupport oncogenic signaling for advanced progression of breast and prostate cancers. Intensive studies haveuncovered cellular and biochemical changes underlying the development of hormone resistance. However,epigenetic mechanisms for establishing and maintaining a hormone-resistant phenotype remain to beexplored.

Microtubule stabilizing agents (MSAs) are some of the most widely used and effective therapies availablefor the treatment of solid tumors. However, their utility is compromised by innate and acquired drugresistance. The taccalonolides (taccas) are a mechanistically unique class of MSAs that circumventmultiple clinically relevant forms of drug resistance. Multiple potent taccas identified by our laboratorieshave effective antitumor activity in drug sensitive and resistant in vivo models but suffer from a narrowtherapeutic window.