Using Luminal Epithelial Cells Like Canaries in a Coal Mine: Aging Biomarkers for Tracking Bioactivity of Chemoprevention and for Estimates of Cancer Risk
Abstract
This is an Expansion Award proposal based on work stemming from my Era of Hope Scholar Award. It addresses the overarching challenges of breast cancer prevention in the primary contexts, and identification of determinants of breast cancer initiation, risk, or susceptibility. The process of aging makes women more susceptible to breast cancer, and we are working to understand and control the biological basis of that susceptibility. We revealed that, with age, tumor suppressive myoepithelial cells are lost, progenitor cells (the cancer cell-of-origin) accumulate, and luminal epithelial cells lose lineage specificity. These tissue-level changes are associated with specific biochemical, biomechanical, transcriptional, and genome-wide methylation changes. Our preliminary data suggest that breast tissue from young women who are at high risk of breast cancer, e.g., because they are BRCA1mut carriers, exhibit an acceleration of aging-related molecular signatures. Indeed, high-risk tissue effectively appears biologically older than their chronological age by as much as two decades. We hypothesize that the same age-related cell states that make older women more susceptible to cancer also form the biological basis of high-risk breast cancers in younger women. The luminal epithelial lineage, in specific, exhibits the most pronounced age-related phenotypes, and we think they may represent the cellular version of the proverbial “canary in the coal mine.” However, instead of signaling a mine’s safety, they serve as beacons of susceptibility that identify individuals who are at high risk of breast cancer. These cellular beacons also may be useful for detecting biological activity of putative breast cancer chemoprevention agents by measuring their ability to de-accelerate the aging process. If so, it would surmount a practical barrier to performing chemoprevention trials for primary breast cancers -- that is, once a molecule is known to be safe enough to use for everyday prevention, it must be proven to have a biological effect within a reasonable timeframe. We have identified quantifiable measures of the aging process that may also reflect breast cancer risk, and we have shown that the states associated with aging can be modified by a cell non-autonomous mechanism. We will determine whether the measurements of the biochemical, biomechanical, transcriptional, and epigenetic phenotypes of epithelial cells related to aging detect young women who are at high risk for breast cancer, even though they may not have one of the known predisposing mutations. We will test the feasibility for future clinical studies by examining breast epithelial samples obtained using minimally invasive methods. And we will perform retrospective analyses of samples obtained from chemoprevention clinical trials conducted in high-risk patients. Aim 1: My collaborator Dr. Lydia Sohn developed a microfluidic device that measures five mechanical properties of cells at single cell resolution. We have shown that mammary epithelia possess unique mechanical properties change that vary by lineage, age, and stage of malignant progression. These measurements are made rapidly, and on small numbers of cells. We will determine if machine learning algorithms can detect a mechanical signature that distinguishes normal-risk and high-risk breast tissue. Aim 2: To be useful clinically, measures of biological age must work in samples of breast cells that can be reasonably obtained from women in a chemoprevention trial. Retro periaereolar fine needle aspirates (RPFNA) and ductal lavages (DL) are two minimally invasive means to obtaining epithelial cells from breast. My collaborator Dr. Victoria Seewaldt and I have been collecting de-identified RPFNAs and matched discarded breast tissue from which we grow the primary HMEC (human mammary epithelial cell) strains that are the basis of the preceding work. Dr. Susan Love has provided us with >800 DL specimens from wom
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910593
Entities
People
- Mark A LaBarge
Organizations
- Beckman Research Institute of City of Hope
- United States Army