The Histone Demethylase LSD1/ΚDM1A Mediates Chemoresistance in Breast Cancer via Regulation of a Stem Cell Program

Abstract

Breast cancer is the leading cause of cancer death in the female population, despite advances in diagnosis and treatment. The highly heterogeneous nature of the disease represents a major obstacle to successful therapy and results in a significant number of patients developing drug resistance and, eventually, suffering from tumor relapse. Cancer stem cells (CSCs) are a small subset of tumor cells characterized by self-renewal, increased tumor-initiation capacity, and resistance to conventional therapies. As such, they have been implicated in the etiology of tumor recurrence and have emerged as promising targets for the development of novel therapies. Here, we show that the histone demethylase lysine-specific demethylase 1 (LSD1) plays an important role in the chemoresistance of breast cancer cells. Our data, from a series of in vitro and in vivo assays, advocate for LSD1 being critical in maintaining a pool of tumor-initiating cells that may contribute to the development of drug resistance. Combinatory administration of LSD1 inhibitors and anti-cancer drugs is more efficacious than monotherapy alone in eliminating all tumor cells in a 3D spheroid system. In conclusion, we provide compelling evidence that LSD1 is a key regulator of breast cancer stemness and a potential target for the design of future combination therapies.

LSD1/KDM1A, a Gate-Keeper of Cancer Stemness and a Promising Therapeutic Target

“…Interestingly, combination treatment of mouse xenografts with the drug and an LSD1 inhibitor led to reduction of tumor volume [105]. Similar data on LSD1 regulation of b-CSCs and its therapeutic potential were also obtained by our group [106]. LSD1 knock-down and pharmacological inhibition impaired the stemness properties and significantly reduced the number of CD44 + -CD24 -CSCs in vitro.…”

“…More interestingly, by in vitro manipulation of the LSD1 levels, we showed that it conferred increased chemoresistance to breast cancer cells. Using a 3D tumorsphere system, we also demonstrated that combined administration of an LSD1 inhibitor (2-PCPA or GSK-LSD1) and a conventional drug (doxorubicin or paclitaxel) had a synergistic effect and led to a significant reduction in their number, while it targeted the CSC-subpopulation [106].…”

“…Similarly, in the solid tumor preclinical reports covered in this review, treatment schemes with LSD1 inhibitors alone [95,101,115] or in combination with other drugs [105,106,130] produced impressive results with therapeutic potential that is reflected in the long list of ongoing clinical trials in a range of human cancers (Table 2).…”

“…However, it should be pointed out that these clinical studies do not include functional assays that can assess this parameter yet. Similarly, in most of the pre-clinical studies on LSD1 inhibition [83,131,132] the outcome is usually evaluated through its bulk characteristics i.e., tumor growth/volume, survival, dosing, and toxicity, leaving the effect on the CSC content elusive, with a few exceptions [105,106]. In our opinion, the solid findings provided by the basic research reports we presented herein prove that the regulation of CSCs by LSD1 is an important aspect of its role in cancer and it should be evaluated in all preclinical and clinical future studies.…”

Phase I Study of Lysine-Specific Demethylase 1 Inhibitor, CC-90011, in Patients with Advanced Solid Tumors and Relapsed/Refractory Non-Hodgkin Lymphoma

“…The importance of LSD1 in differentiation suggests that dysregulation of LSD1 activity may alter pathways associated with stem-cell-like phenotypes (8). In support of this, overexpression of LSD1 has been shown to promote cell proliferation, migration, and invasion in a variety of human cancers (4,(8)(9)(10)(11)(12)(13)(14).…”