Determining the effects of pregnancy and aging on the mammary gland

University Of California Santa Cruz, Santa Cruz CA

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT The long-term goal of this proposal is to elucidate the molecular and cellular processes underlying breast cancer risk reduction by an early full-term pregnancy. Specifically, the objective of this project is to determine the impact of age and pregnancy on mammary epithelial cells (MECs). Preliminary analysis of bulk single-cell RNA sequencing data from 18 month old nulliparous (no pregnancy) and 18 month old parous (at least 2 pregnancies) reveals that pregnancy induces a persistent inflammatory and differentiated state in MECs. Intriguingly, luminal MECs from aged, parous mice exhibit heightened inflammatory signaling but reduced proliferative capacity when challenged with TNFα. I have also identified a minority population of Krt6a+ hybrid MECs that increase with age but are lost in parous mice. Building on these exciting preliminary results, I hypothesize that an early pregnancy alters the aging trajectory of stem/progenitor MECs to induce differentiation and inflammation programs that reduce cellular plasticity and oncogenic vulnerability. Aim 1 will determine the impact of aging and pregnancy on TNFα-mediated inflammatory responses and oncogenic vulnerability in MECs. Aim 1A will determine whether Tnfrsf11b, an inhibitor of TNFα-induced apoptosis that is downregulated in aged, parous luminal cells, is responsible for the restricted growth of TNFα-treated luminal organoids from aged, parous mice. Aim 1B further explores whether the altered inflammatory profile in aged, parous MECs diminishes their tumor initiation capacity, a critical factor in understanding breast cancer risk dynamics. Aim 2 addresses the roles of Krt6a+ hybrid MECs in lineage plasticity and oncogenesis. Preliminary data show that Krt6a+ hybrid cells accumulate with age but are lost by pregnancy. Recent studies highlight the importance of lineage plasticity as a precursor to tumor initiation, providing a unique angle for understanding the dynamics of breast cancer protection. Aim 2A investigates whether the pregnancy-induced reduction of Krt6a+ cells lessens tumor burden by inducing specific mutations. Aim 2B explores the roles of unique Krt6a+ genes, Aldh3a1 and Il33, in maintaining a plastic cell state through overexpression and knock-down assays. This approach aims to define the role of Krt6a+ progenitors in pregnancy-induced protection in breast cancer, potentially serving as a future biomarker. In summary, this project will address the significant gap in understanding how an early full-term pregnancy alters age- induced senescence pathways in the mammary gland to ultimately reduce breast cancer risk. The experiments will be conducted under the guidance of Dr. Shaheen Sikandar and with the exceptional resources provided by UC Santa Cruz. This proposal not only has the potential to illuminate the dynamics of breast cancer vulnerability, but the training opportunity also places me in a position to develop into a self-directed and independent scientist.