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.
Highlights
Breast cancer is the most commonly occurring malignancy in women and, recently, it has become the leading cause of cancer-associated deaths worldwide, surpassing the fatality of lung cancer in the female population [1]
Subsequent studies showed that lysine-specific demethylase 1 (LSD1) levels were elevated during tumor progression of ductal carcinoma [34] and established that high LSD1 levels correlated with poor prognosis in breast cancer patients [35,36]
The LSD1 mRNA levels were significantly increased in specimens from patients with invasive breast cancer compared to normal breast tissue samples [38] (Figure S1A)
Summary
Breast cancer is the most commonly occurring malignancy in women and, recently, it has become the leading cause of cancer-associated deaths worldwide, surpassing the fatality of lung cancer in the female population [1]. Breast tumors from different patients manifest significant diversity on the phenotypic and transcriptional levels, leading to their early classification into histological types and, to the more recent, identification of intrinsic molecular subtypes, respectively [2] This information on inter-tumoral heterogeneity has had a major impact on the therapeutic decision-making process and it has greatly improved disease management and overall patient survival [3]. This intra-tumoral heterogeneity, accounts largely for the observation that some breast cancer patients respond, initially, well to treatment, but later succumb to tumor relapse and metastasis [5] This may be due to the presence of therapy-resistant cancer cells that are not sufficiently eliminated by conventional treatment schemes and drive tumor regrowth and development of metastatic lesions [6]. Of critical importance to delineate the mechanisms that underlie the malignant properties of these cells, and thereby pave the way for the development of novel, therapeutic modalities targeted against them
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