Adaptation to Hypoxia May Promote Therapeutic Resistance to Androgen Receptor Inhibition in Triple-Negative Breast Cancer

Abstract

Triple-negative breast cancer (TNBC) surpasses other BC subtypes as the most challenging to treat due to its lack of traditional BC biomarkers. Nearly 30% of TNBC patients express the androgen receptor (AR), and the blockade of androgen production and AR signaling have been the cornerstones of therapies for AR-positive TNBC. However, the majority of women are resistant to AR-targeted therapy, which is a major impediment to improving outcomes for the AR-positive TNBC subpopulation. The hypoxia signaling cascade is frequently activated in the tumor microenvironment in response to low oxygen levels; activation of the hypoxia signaling cascade allows tumors to survive despite hypoxia-mediated interference with cellular metabolism. The activation of hypoxia signaling networks in TNBC promotes resistance to most anticancer drugs including AR inhibitors. The activation of hypoxia network signaling occurs more frequently in TNBC compared to other BC subtypes. Herein, we examine the (1) interplay between hypoxia signaling networks and AR and (2) whether hypoxia and hypoxic stress adaptive pathways promote the emergence of resistance to therapies that target AR. We also pose the well-supported question, “Can the efficacy of androgen-/AR-targeted treatments be enhanced by co-targeting hypoxia?” By critically examining the evidence and the complex entwinement of these two oncogenic pathways, we argue that the simultaneous targeting of androgen biosynthesis/AR signaling and hypoxia may enhance the sensitivity of AR-positive TNBCs to AR-targeted treatments, derail the emergence of therapy resistance, and improve patient outcomes.

Racial Disparity in Quadruple Negative Breast Cancer: Aggressive Biology and Potential Therapeutic Targeting and Prevention

“…Darolutamide antagonizes AR mutants such as F876 L, W741L, and T877A [ 42 ]. Apalutamide and darolutamide are currently under evaluation as promising new-generation AR inhibitors in phase III clinical trials for non-metastatic castration-resistant prostate cancer (NCT01946204 and NCT02200614, respectively) [ 43 ]. Thus, these new AR inhibitors may be tested in AR-positive TNBC patients in the future.…”

CMA mediates resistance in breast cancer models

“…HIF-1α is overexpressed in hypoxic conditions and drives the expression of a pool of genes involved in the adaptation of tumour cells to a hypoxic milieu supporting also the ability of cancer cells to escape treatment toxicity [ 20 ]. Moreover, HIF-1α plays a pivotal role in cancer onset, development, progression [ 21 – 23 ] and its association with resistance in BC and other pathologies has been molecularly elucidated [ 24 , 25 ]. On the other hand, HIF-1α decrease is associated with the reduction of cell proliferation and aggressiveness and a corresponding increased susceptibility to radio and chemo-therapeutic treatment protocols.…”