Estrogen Receptor Expression Is Associated with DNA Repair Capacity in Breast Cancer.

Jaime Matta,Damian Adams,Patricia Casbas,Luisa Morales,Erick Suárez,Julie Dutil,Miguel Echenique,Wanda Vargas,Carmen Ortiz,William B Coleman

doi:10.1371/journal.pone.0152422

Abstract

Estrogen-receptor-positive (ER+) tumors employ complex signaling that engages in crosstalk with multiple pathways through genomic and non-genomic regulation. A greater understanding of these pathways is important for developing improved biomarkers that can better determine treatment choices, risk of recurrence and cancer progression. Deficiencies in DNA repair capacity (DRC) is a hallmark of breast cancer (BC); therefore, in this work we tested whether ER signaling influences DRC. We analyzed the association between ER positivity (% receptor activation) and DRC in 270 BC patients, then further stratified our analysis by HER2 receptor status. Our results show that among HER2 negative, the likelihood of having low DRC values among ER- women is 1.92 (95% CI: 1.03, 3.57) times the likelihood of having low DRC values among ER+ women, even adjusting for different potential confounders (p<0.05); however, a contrary pattern was observed among HER2 positives women. In conclusion, there is an association between DRC levels and ER status, and this association is modified by HER2 receptor status. Adding a DNA repair capacity test to hormone receptor testing may provide new information on defective DNA repair phenotypes, which could better stratify BC patients who have ER+ tumors. ER+/HER2- tumors are heterogeneous, incompletely defined, and clinically challenging to treat; the addition of a DRC test could better characterize and classify these patients as well as help clinicians select optimal therapies, which could improve outcomes and reduce recurrences.

Highlights

Worldwide, breast cancer (BC) is a growing health problem, both in its increasing incidence [1] and resistance to treatment [2]
The relationship between estrogen receptor (ER) activation/signaling and DNA damage/repair is only starting to be investigated. This manuscript: (1) explains our recent findings regarding the association between ER status and the defective DNA repair phenotype, controlling for different variables including human epidermal growth factor receptor 2 (HER2) receptor status [38,39], (2) outlines potential mechanisms behind what we found for future mechanistic studies, and (3) proposes how our findings could form the basis for a new combination of biomarker testing that may better characterize BC tumors, which could improve diagnostic, prognostic, and therapeutic efforts
18.5% were younger than 45 years and 24.4% were older than 65 years

Summary

Introduction

Breast cancer (BC) is a growing health problem, both in its increasing incidence [1] and resistance to treatment [2]. Most ER+ breast tumors are classified as luminal [13,14,15,41]. Luminal A is characterized by ER +/PR+/HER2-/low Ki-67 [42] and typically responds well to endocrine therapy [28]. Luminal B is either HER2+ or HER2- but is ER+/PR+/high Ki-67 [42]; such tumors are complex diagnostically and therapeutically [28]. Lips’ 2012 analysis of biopsies from 211 treatment-naïve ER+/HER2- primary breast tumors could not define a subgroup that would be most likely to benefit from neoadjuvant therapy, much less predict chemosensitivity or treatment outcome. Biopsies of the same patients taken post-treatment but prior to surgery were unrevealing [41]

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Discussion

Conclusion