Hepatocyte growth factor pathway expression in breast cancer by race and subtype

Gieira S Jones,Michael I Love,Melissa A Troester,Alina M Hamilton,Erin L Kirk,Linnea T Olsson,Andrew F Olshan,Heather J Tipaldos,Hazel B Nichols,Katherine A Hoadley,Jodie M Fleming,Arjun Bhattacharya

doi:10.1186/s13058-021-01460-5

Abstract

BackgroundAfrican American women have the highest risk of breast cancer mortality compared to other racial groups. Differences in tumor characteristics have been implicated as a possible cause; however, the tumor microenvironment may also contribute to this disparity in mortality. Hepatocyte growth factor (HGF) is a stroma-derived marker of the tumor microenvironment that may affect tumor progression differentially by race.ObjectiveTo examine whether an HGF gene expression signature is differentially expressed by race and tumor characteristics.MethodsInvasive breast tumors from 1957 patients were assessed for a 38-gene RNA-based HGF gene expression signature. Participants were black (n = 1033) and non-black (n = 924) women from the population-based Carolina Breast Cancer Study (1993–2013). Generalized linear models were used to estimate the relative frequency differences (RFD) in HGF status by race, clinical, and demographic factors.ResultsThirty-two percent of tumors were positive for the HGF signature. Black women were more likely [42% vs. 21%; RFD = + 19.93% (95% CI 16.00, 23.87)] to have HGF-positive tumors compared to non-black women. Triple-negative patients had a higher frequency of HGF positivity [82% vs. 13% in non-triple-negative; RFD = + 65.85% (95% CI 61.71, 69.98)], and HGF positivity was a defining feature of basal-like subtype [92% vs. 8% in non-basal; RFD = + 81.84% (95% CI 78.84, 84.83)]. HGF positivity was associated with younger age, stage, higher grade, and high genomic risk of recurrence (ROR-PT) score.ConclusionHGF expression is a defining feature of basal-like tumors, and its association with black race and young women suggests it may be a candidate pathway for understanding breast cancer disparities.

Highlights

The tumor microenvironment can promote carcinogenesis by secretion of stroma-derived factors that are master regulators of cell division, growth, motility, and morphology [1]
Black women were more likely [42% vs. 21%; relative frequency differences (RFD) = + 19.93%] to have Hepatocyte growth factor (HGF)-positive tumors compared to non-black women
Triplenegative patients had a higher frequency of HGF positivity [82% vs. 13% in non-triple-negative; RFD = + 65.85%], and HGF positivity was a defining feature of basal-like subtype [92% vs. 8% in non-basal; RFD = + 81.84%]

Summary

Introduction

The tumor microenvironment can promote carcinogenesis by secretion of stroma-derived factors that are master regulators of cell division, growth, motility, and morphology [1]. Hepatocyte growth factor (HGF) is one of the major components secreted by the tumor stroma that drives tumorigenesis [1,2,3,4,5]. In breast cancer cell lines, activation of the HGF pathway via binding of HGF to its receptor cMET can lead to increased cell survival, proliferation, and resistance to cancer inhibitors [1]. Clinical studies have correlated activation of the HGF pathway (as defined by c-MET over-expression) with increased tumor size, high tumor grade, and distant metastasis [6]. Hepatocyte growth factor (HGF) is a stromaderived marker of the tumor microenvironment that may affect tumor progression differentially by race

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Discussion

Conclusion