Use of endocrine therapy for estrogen receptor-positive breast cancer among American Indians and Alaska natives.

BACKGROUND: American Indian/Alaska Native (AI/AN) women with estrogen receptor-positive (ER +) breast cancer have higher mortality compared to non-Hispanic whites (NHW). The purpose of this study is to compare rates of initiation of endocrine therapy (ET) between AI/AN and NHW and further determine survival outcomes for ER + breast cancer. METHODS: We used the National Cancer Database to identify patients diagnosed with ER + breast cancer, stage I-III, between 2004 and 2017. Multivariable logistic regression was performed to determine factors associated with initiation of adjuvant ET. Overall survival was estimated using the Kaplan-Meier analysis and Cox proportional hazards modeling. RESULTS: We identified a total of 771,619 patients (AI/AN, n = 2473; NHW, n = 769,146). Compared to NHW, AI/AN patients were more likely to live in rural areas, be younger, and have tumors that were higher grade, node positive, and larger. Initiation of adjuvant ET was high in both groups and not significantly different between AI/AN and NHW. Independent predictors of ET initiation included rural location, age, higher tumor grade, node-positive disease, larger tumor size, and progesterone receptor-positive status. Initiation of ET was significantly associated with improved overall survival among all patients. Overall survival was significantly worse among the AI/AN population. CONCLUSION: AI/AN race was significantly and independently associated with worse overall survival after diagnosis of ER + breast cancer. We did not find a significant difference in the initiation of adjuvant ET between AI/AN and NHW. Exact reasons why AI/AN women with ER + breast cancer have higher mortality rates remain elusive but are probably multifactorial.

USP44 Stabilizes DDB2 to Facilitate Nucleotide Excision Repair and Prevent Tumors.

Nucleotide excision repair (NER) is a pathway involved in the repair of a variety of potentially mutagenic lesions that distort the DNA double helix. The ubiquitin E3-ligase complex UV-DDB is required for the recognition and repair of UV-induced cyclobutane pyrimidine dimers (CPDs) lesions through NER. DDB2 directly binds CPDs and subsequently undergoes ubiquitination and proteasomal degradation. DDB2 must remain on damaged chromatin, however, for sufficient time to recruit and hand-off lesions to XPC, a factor essential in the assembly of downstream repair components. Here we show that the tumor suppressor USP44 directly deubiquitinates DDB2 to prevent its premature degradation and is selectively required for CPD repair. Cells lacking USP44 have impaired DDB2 accumulation on DNA lesions with subsequent defects in XPC retention. The physiological importance of this mechanism is evident in that mice lacking Usp44 are prone to tumors induced by NER lesions introduced by DMBA or UV light. These data reveal the requirement for highly regulated ubiquitin addition and removal in the recognition and repair of helix-distorting DNA damage and identify another mechanism by which USP44 protects genomic integrity and prevents tumors.