Abstract
27-hydroxycholesterol (27HC), synthesized from cholesterol by the enzyme CYP27A1, differentially impacts estrogen receptor positive (ER+) breast cancer (BC) cell growth depending on estrogen levels. This study examined the association between CYP27A1 expression and prognosis in a cohort of 193 premenopausal patients with lymph node-negative primary BC with limited exposure to adjuvant systemic cancer treatments. In multivariable analyses among patients with ER+ tumors, high CYP27A1 protein and mRNA expressions were associated with four- and eight-fold reductions in the incidence of distant recurrence-free survival events: HRadj = 0.26, 95% CI = 0.07–0.93 and HRadj = 0.13, 95% CI = 0.03–0.60, respectively. In vitro studies revealed that 27HC treatment potently inhibited ER+ BC cell proliferation under lipid-depleted conditions regardless of estradiol levels, transcriptionally mediated through the downregulation of ER signaling with a concomitant upregulation of cholesterol export. Importantly, if validated, these results may have implications for adjuvant treatment decisions in premenopausal patients, especially when de-escalation of therapy is being considered.
Highlights
Breast cancer (BC) is characterized by marked heterogeneity at the molecular and morphological levels, dictating varied prognosis and requiring diverse therapeutic interventions
We have evaluated the independent impact of CYP27A1 protein and transcript expression on the prognosis of primary invasive BC among premenopausal patients with lymph node-negative disease
The incidence of disease recurrence and/or death among patients presenting with ER+ BC was reduced by more than a factor of two for patients with CYP27A1 high tumors compared to patients with CYP27A1 low tumors
Summary
Breast cancer (BC) is characterized by marked heterogeneity at the molecular and morphological levels, dictating varied prognosis and requiring diverse therapeutic interventions. BC is classified into distinct clinical subtypes based on the expression of hormone receptors and human epidermal growth factor receptor 2 (HER2)[1,2]. Estrogen receptor positive (ER+) disease is the most common subtype[3] and is driven by direct interactions between the ligand estrogen and its cognate receptor, ER, that leads to the transcriptional activation of genes central to cell growth and survival[4]. Because of the lack of accurate treatment predictive and prognostic biomarkers, over-treatment of patients remains a clinical challenge, as all treatments are associated with undesirable side effects[8]. There is a constant search for novel biomarkers to further refine prognostication and tailor treatments on an individual basis if possible
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