Hypoxia-inducible factor-1\u03b1 expression and breast cancer recurrence in a Danish population-based case control study

Lindsay J Collin,Peer M Christiansen,Maret L Maliniak,Thomas P Ahern,Kristina B Christensen,Henrik Toft Sørensen,Sinna P Ulrichsen,Rami Yacoub,Timothy L Lash,Per Damkier,Deirdre P Cronin-Fenton,Stephen Hamilton-Dutoit

doi:10.1186/s13058-021-01480-1

Abstract

BackgroundHypoxia-inducible factor-1α (HIF-1α) is a transcription factor that facilitates the adaptation of cancer cells to hypoxic conditions and may be prognostic of breast cancer recurrence. We evaluated the association of HIF-1α expression with breast cancer recurrence, and its association with timing of breast cancer recurrence.MethodsIn this population-based case-control study, we included women diagnosed with stage I–III breast cancer between 1985 and 2001, aged 35–69 years, registered in the Danish Breast Cancer Group. We identified 541 cases of breast cancer recurrence among women with estrogen receptor (ER)-positive disease who were treated with tamoxifen for at least 1 year (ER+ TAM+). We also enrolled 300 breast cancer recurrence cases among women with ER-negative disease, not treated with tamoxifen, who survived at least 1 year (ER−/TAM−). Controls were recurrence-free breast cancer patients at the time of case diagnosis, matched to recurrence cases on ER/TAM status, date of surgery, menopausal status, cancer stage, and county of residence. Expression of HIF-1α was measured by immunohistochemistry on tissue microarrays. We fitted logistic regression models to compute odds ratios (ORs) and 95% confidence intervals (CIs) associating HIF-1α expression with recurrence, and with timing of recurrence.ResultsHIF-1α expression was observed in 23% of cases and 20% of controls in the ER+/TAM+ stratum, and in 47% of cases and 48% of controls in the ER−/TAM− stratum. We observed a near-null association between HIF-1α expression in both ER/TAM groups (ER+/TAM+ OR = 1.21, 95%CI 0.88, 1.67 and ER−/TAM− OR = 0.97, 95%CI 0.68, 1.39). HIF-1α expression was not associated with time to recurrence among women in the ER+/TAM+ stratum, but was associated with early recurrence among women in the ER−/TAM− stratum.ConclusionIn this study, HIF-1α expression was not associated with breast cancer recurrence overall but may be associated with early recurrence among women diagnosed with ER− breast cancer.

Highlights

90% of women diagnosed with breast cancer survive more than 10 years after their diagnosis [1]
In the estrogen receptor (ER)+/TAM+ stratum, positive Hypoxia-inducible factor-1α (HIF-1α) expression was observed in 23% of the cases and 20% of the controls, whereas in the ER−/TAM− stratum, we observed that 47% of cases and 48% of controls had positive HIF-1α expression (Table 1)
The majority (96%) of participants were initially diagnosed with stage II or III breast cancer

Summary

Introduction

90% of women diagnosed with breast cancer survive more than 10 years after their diagnosis [1]. Targeted treatment protocols have contributed to improved survival, approximately 20–40% of breast cancer patients will have a recurrence by 20 years after their initial diagnosis [2, 3]. This substantial and Collin et al Breast Cancer Res (2021) 23:103 prolonged risk of recurrence contributes to distress among breast cancer survivors [4]. Hypoxia-inducible factor 1 (HIF-1α) is a transcription factor that facilitates the adaptation of cancer cells to hypoxic conditions [7], and may serve as a prognostic marker for late recurrence [8]. Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that facilitates the adaptation of cancer cells to hypoxic conditions and may be prognostic of breast cancer recurrence. We evaluated the association of HIF-1α expression with breast cancer recurrence, and its association with timing of breast cancer recurrence

Methods

Results

Discussion

Conclusion