Endocrine resistance in hormone-responsive breast cancer: mechanisms and therapeutic strategies

Murphy, Conleth G.; Dickler, Maura N.

doi:10.1530/erc-16-0121

Cited by 102 publications

(79 citation statements)

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“…Hormone sensitive breast cancer has a strong correlation with lower tumor grade; lower levels of amplification of the human epidermal growth factor receptor 2 ( HER2 ) oncogene and concomitant loss of p53 tumor suppressor gene; expression of progesterone receptor (PR), soft tissue and bone metastases and slower rates of disease recurrence. In cases of hormone positive breast cancer along with the expression of ER, multigene tests may be carried out to make treatment decisions particularly for adjuvant therapy and screen those patients who would benefit more from combination of endocrine plus chemotherapy[24-26]. …”

Section: Introductionmentioning

confidence: 99%

Targeted therapies in breast cancer: New challenges to fight against resistance

Masoud

Pagès

2017

WJCO

242

148

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Breast cancer is the most common type of cancer found in women and today represents a significant challenge to public health. With the latest breakthroughs in molecular biology and immunotherapy, very specific targeted therapies have been tailored to the specific pathophysiology of different types of breast cancers. These recent developments have contributed to a more efficient and specific treatment protocol in breast cancer patients. However, the main challenge to be further investigated still remains the emergence of therapeutic resistance mechanisms, which develop soon after the onset of therapy and need urgent attention and further elucidation. What are the recent emerging molecular resistance mechanisms in breast cancer targeted therapy and what are the best strategies to apply in order to circumvent this important obstacle? The main scope of this review is to provide a thorough update of recent developments in the field and discuss future prospects for preventing resistance mechanisms in the quest to increase overall survival of patients suffering from the disease.

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Section: Introductionmentioning

confidence: 99%

Targeted therapies in breast cancer: New challenges to fight against resistance

Masoud

Pagès

2017

WJCO

242

148

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“…Mediators of endocrine resistance include loss of expression or genomic aberration (for example, mutations) of ER, altered expression of ER co-regulators and cell cycle signaling molecules, increased signaling of growth factor receptor pathways, and enhanced autophagy [10–12]. There have been only a limited number of studies testing the mechanism of anti-estrogen resistance in ILC, identifying potential roles for signaling through estrogen-related receptor gamma (ERRγ) [13], ERβ [14], FGFR1 [15, 16], and MAPK1 [17].…”

Section: Introductionmentioning

confidence: 99%

Key regulators of lipid metabolism drive endocrine resistance in invasive lobular breast cancer

Sikora

Levine

et al. 2018

Breast Cancer Res

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BackgroundInvasive lobular breast carcinoma (ILC) is a histological subtype of breast cancer that is characterized by loss of E-cadherin and high expression of estrogen receptor alpha (ERα). In many cases, ILC is effectively treated with adjuvant aromatase inhibitors (AIs); however, acquired AI resistance remains a significant problem.MethodsTo identify underlying mechanisms of acquired anti-estrogen resistance in ILC, we recently developed six long-term estrogen-deprived (LTED) variant cell lines from the human ILC cell lines SUM44PE (SUM44; two lines) and MDA-MB-134VI (MM134; four lines). To better understand mechanisms of AI resistance in these models, we performed transcriptional profiling analysis by RNA-sequencing followed by candidate gene expression and functional studies.ResultsMM134 LTED cells expressed ER at a decreased level and lost growth response to estradiol, while SUM44 LTED cells retained partial ER activity. Our transcriptional profiling analysis identified shared activation of lipid metabolism across all six independent models. However, the underlying basis of this signature was distinct between models. Oxysterols were able to promote the proliferation of SUM44 LTED cells but not MM134 LTED cells. In contrast, MM134 LTED cells displayed a high expression of the sterol regulatory element-binding protein 1 (SREBP1), a regulator of fatty acid and cholesterol synthesis, and were hypersensitive to genetic or pharmacological inhibition of SREBPs. Several SREBP1 downstream targets involved in fatty acid synthesis, including FASN, were induced, and MM134 LTED cells were more sensitive to etomoxir, an inhibitor of the rate-limiting enzyme in beta-oxidation, than their respective parental control cells. Finally, in silico expression analysis in clinical specimens from a neo-adjuvant endocrine trial showed a significant association between the increase of SREBP1 expression and lack of clinical response, providing further support for a role of SREBP1 in the acquisition of endocrine resistance in breast cancer.ConclusionsOur characterization of a unique series of AI-resistant ILC models identifies the activation of key regulators of fatty acid and cholesterol metabolism, implicating lipid-metabolic processes driving estrogen-independent growth of ILC cells. Targeting these changes may prove a strategy for prevention and treatment of endocrine resistance for patients with ILC.Electronic supplementary materialThe online version of this article (10.1186/s13058-018-1041-8) contains supplementary material, which is available to authorized users.

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“…Various mechanisms are responsible for either acquired or de novo resistance to endocrine therapy, including mutations in ESR1, amplification and overexpression of growth factor receptors (GFRs), and alterations in cell cycle machinery (11). Activated growth factor receptor pathways, such as human epidermal growth factor receptor-2 (HER2), insulin-like growth factor 1 receptor (IGF1R), and fibroblast GFR 1 (FGFR1), converge on the PI3K/Akt/mTOR and Raf/Mek/Erk pathways to support tumor cell proliferation and survival after estrogen deprivation and serve as current targets of approved therapies for steroid hormone receptor-positive disease.…”

Section: Introductionmentioning

confidence: 99%