RNA-based TP53 pathway function, estrogen receptor status, and breast cancer risk and progression

Background: TP53 and estrogen receptor (ER) both play essential roles in breast cancer development and progression, with recent research revealing crosstalk between these two signaling pathways. Risk factor and survival associations by TP53 status have been inconsistent, with few studies using RNA-based TP53 classification methods. Methods: Aim 1 was to identify clinical characteristics and epidemiologic risk factors associated with RNA-based TP53 status, while also considering ER status. This case-only analysis included 4,466 incident breast cancer cases from the Carolina Breast Cancer Study (CBCS). The RNA-based results were compared to those when using IHC-based TP53 classification methods. Aim 2 was to evaluate differences in breast cancer survival by RNA-based TP53 status, stratified by ER status. Participants included 3,213 women in CBCS at stage I-III at diagnosis. Findings in the population-based CBCS were validated in a the METABRIC study (N=1,343). The RNA-based results were compared to those when using IHC- and DNA-based TP53 classification methods. Results: For Aim 1, several hormone-related factors (oral contraceptive use, menopausal status, age at menopause, and pre- and post-menopausal BMI) were associated with RNA-based TP53 status, while reproductive factors (age at first birth and parity) and smoking status were associated with ER status. Multiparity was associated with both TP53 and ER. When classifying TP53 status using IHC methods, no associations were observed with TP53 status. For Aim 2, TP53 mutant-like cases had poorer breast cancer-specific survival compared to wildtype-like cases. This survival difference by TP53 status was slightly stronger among ER-negative compared to ER-positive cases. Survival effects were attenuated when using DNA-based or IHC-based TP53 classification. Survival effects in METABRIC were weaker than those observed in CBCS, with the survival effect limited to ER positive cases only. Conclusions: We found evidence of etiologic heterogeneity across breast cancer subtypes defined by RNA-based TP53 status and ER status. We also found RNA-based TP53 to be a strong prognostic marker within both ER positive and negative cases. These markers may represent an important etiologic schema in breast cancer prevention research and may add value for clinical prognostication.Doctor of Philosoph