Cancer stem cells: Culprits in endocrine resistance and racial disparities in breast cancer outcomes

Highlights

• Endocrine therapy is highly efficacious though some patients experience relapse.

• Breast cancer stem cells (BCSCs) contribute to endocrine resistance and relapse.

• BCSCs likely play a causal role in racial disparities observed in breast cancer.

• Targeting BCSCs is expected to improve luminal breast cancer patient outcomes.

Abstract

Breast cancer stem cells (BCSCs) promote endocrine therapy (ET) resistance, also known as endocrine resistance in hormone receptor (HR) positive breast cancer. Endocrine resistance occurs via mechanisms that are not yet fully understood. In vitro, in vivo and clinical data suggest that signaling cascades such as Notch, hypoxia inducible factor (HIF), and integrin/Akt promote BCSC-mediated endocrine resistance. Once HR positive breast cancer patients relapse on ET, targeted therapy agents such as cyclin dependent kinase inhibitors are frequently implemented, though secondary resistance remains a threat. Here, we discuss Notch, HIF, and integrin/Akt pathway regulation of BCSC activity and potential strategies to target these pathways to counteract endocrine resistance. We also discuss a plausible link between elevated BCSC-regulatory gene levels and reduced survival observed among African American women with basal-like breast cancer which lacks HR expression. Should future studies reveal a similar link for patients with luminal breast cancer, then the use of agents that impede BCSC activity could prove highly effective in improving clinical outcomes among African American breast cancer patients.

Introduction

More than 500,000 women die from breast cancer each year worldwide. Most women are diagnosed with hormone receptor (HR) positive or luminal breast cancer since their tumors express the estrogen receptor (ER), the progesterone receptor (PR), and in rarer instances, human epidermal growth factor receptor 2 (Her2). Luminal breast cancer is further divided into two subtypes: luminal A and luminal B, with the luminal A subtype exhibiting the best prognosis [1]. Endocrine therapy (ET) entails blocking the binding of estrogen to the ER often designated as estrogen receptor alpha (ERα), or inhibiting aromatase which converts androgens into estrogens.

Selective estrogen receptor modulator tamoxifen, acts as an estrogen antagonist in breast tissues yet behaves as an estrogen agonist in cardiac tissues and bone [2]. Aromatase inhibitors (AIs) have largely replaced tamoxifen as first line therapy for luminal breast cancer due to their enhanced efficacy [3]. Thus, tamoxifen is primarily used in women who cannot tolerate AIs. In pre-menopausal patients, AIs alone are insufficient to decrease estrogen levels due to the production of estrogen from the ovaries. It is therefore necessary to suppress ovarian function, which is commonly and reversibly achieved using luteinizing hormone-releasing hormone analogs. Patients who develop AI resistance are often treated with the selective estrogen receptor down-regulator fulvestrant in combination with agents such as cyclin dependent kinase (CDK) inhibitors [4].

Though ET often shows tremendous efficacy, relapse occurs in more than 40% of patients [5]. When patients develop resistance to one form of ET, they are often treated with an alternate form of ET. However, resistance to alternate forms of ET frequently occurs. Emerging evidence suggests that ET often enriches the breast cancer stem cell (BCSC) population to ultimately promote relapse [6] (Fig. 1A). Recently, AI-resistant cells were shown to exhibit high levels of stemness markers [7]. To eradicate BCSCs, it is necessary to identify cellular signaling pathways that promote BCSC development and function [8].

African American women experience higher rates of breast cancer mortality than European American women despite lower overall incidence [9]. Differences in tumor biology are believed to contribute to this survival disparity. This minireview will focus on molecular aberrations within breast cancer cells that promote stem cell survival and increase the risk of endocrine resistance onset. We will discuss the potential contribution of BCSCs to the breast cancer survival disparity observed among African American women. We will also discuss potential therapeutic strategies to overcome endocrine resistance based on preclinical and clinical studies.