Collagen Sequence Variants in Racial Disparities of Breast Cancer

In breast cancer, collagen re-alignment is predictive of subtype, outcome and recurrence with limited data on
contribution to racial disparities. For African-American (AA) women, breast cancer mortality is higher than any
other race/ethnicity, in spite of having lower incidence rates. A disproportionate number of African-American
women are affected by aggressive metastatic triple negative breast cancer (TNBC) without significant knowledge
of mechanisms driving this ancestry-dependent difference. Collagen processing is a primary feature of TNBC
tumors with increases in tumor adjacent collagen deposition, altered tumor-stroma ratios, and re-alignment of
collagen fibers at tumor borders leading to metastasis. However, a knowledge gap exists on understanding
ancestry-dependent translational and post-translational mechanisms of the collagen structure in any breast
cancer type progression. Our preliminary data reports, for the first time, that post-translational regulation of the
collagen triple helical structure by hydroxylated prolines (HYP) is a defining mechanism of racial disparities in
normal and TNBC tissue. Consequently, this proposal focuses on identifying ancestry-dependent translational
and post-translational mechanisms of collagen re-alignment that can ultimately be used to predict and potentially
prevent breast cancer metastasis in AA women. In Aim 1, we will define ancestry dependent post-translational
HYP regulation of collagen sequences from low grade to invasive triple negative breast cancers. Novel
technological platforms will be combined to measure collagen sequences from the tissue microenvironment with
measurement of collagen fiber changes and immune infiltrate. In Aim 2, we will identify HYP post-translational
regulation of collagen sequence variants in ancestry-mapped normal breast tissue stratified by density,
socioeconomic status, marital status, contraceptive use, and risk factors of smoking and alcohol. We will further
determine if collagen sequence variants can be used as a companion scoring metric for prediction of breast
cancer risk. In Aim 3, ancestry-defined normal and metastatic human breast cells will be used to precisely trace
ancestry dependent collagen processing and oncogenic signaling influenced by collagen sequence variants.
This study will increase our understanding of racial disparities in metastatic collagen re-alignment, working to
generate better ancestry-dependent biomarkers for earlier detection of breast cancer and limit mortality due to
breast cancer in minority populations.

Grant Number: 5R01CA253460-05
NIH Institute/Center: NIH
Principal Investigator: Peggi Angel