Endocrine therapy resistance in estrogen receptor (ER)-positive breast cancer

ABSTRACT Acquired endocrine therapy resistance is a significant clinical problem for breast cancer patients. In recent years, increasing attention has been paid to long noncoding RNA (lncRNA) as a critical modulator for cancer progression. Based on RNA-sequencing data of breast invasive carcinomas in The Cancer Genome Atlas database, we identified thymopoietin antisense transcript 1 (TMPO-AS1) as a functional lncRNA that significantly correlates with proliferative biomarkers. TMPO-AS1 positivity analyzed by in situ hybridization significantly correlates with poor prognosis of breast cancer patients. TMPO-AS1 expression was upregulated in endocrine therapy-resistant MCF-7 cells compared with levels in parental cells and was estrogen inducible. Gain and loss of TMPO-AS1 experiments showed that TMPO-AS1 promotes the proliferation and viability of estrogen receptor (ER)-positive breast cancer cells in vitro and in vivo. Global expression analysis using a microarray demonstrated that TMPO-AS1 is closely associated with the estrogen signaling pathway. TMPO-AS1 could positively regulate estrogen receptor 1 (ESR1) mRNA expression by stabilizing ESR1 mRNA through interaction with ESR1 mRNA. Enhanced expression of ESR1 mRNA by TMPO-AS1 could play a critical role in the proliferation of ER-positive breast cancer. Our findings provide a new insight into the understanding of molecular mechanisms underlying hormone-dependent breast cancer progression and endocrine resistance.

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The Omission of Endocrine Therapy (ET) in Older Women with Stage I Estrogen-Receptor (ER)-Positive Breast Cancer Is Not Associated with a Higher Risk of Recurrence

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2019.06.665 ◽

2019 ◽

Vol 105 (1) ◽

pp. E22 ◽

Cited By ~ 1

Author(s):

N.K. Gerber ◽

H. Shao ◽

M. Chadha ◽

H. Gold

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Older Women ◽

Endocrine Therapy ◽

Stage I ◽

Risk Of Recurrence ◽

Er Positive ◽

Positive Breast Cancer

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Breast density change as a predictive surrogate for response to adjuvant endocrine therapy in estrogen receptor-positive breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e21160 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e21160-e21160

Author(s):

Ji sun Kim ◽

Wonshik Han ◽

Jee Man You ◽

Hee-Chul Shin ◽

Soo Kyung Ahn ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Endocrine Therapy ◽

Breast Density ◽

Adjuvant Endocrine Therapy ◽

Absolute Difference ◽

Mammographic Breast Density ◽

Short Term ◽

Er Positive ◽

Positive Breast Cancer

e21160 Background: Previous studies showed that anti-estrogen therapy lowers mammographic breast density (MD). We hypothesized that the short-term change of breast density can be a surrogate marker predicting response to adjuvant endocrine therapy (ET) for breast cancer. Methods: We analyzed data of 1,065 estrogen receptor (ER)-positive breast cancer patients who underwent surgery between 2003 and 2006 and received at least 2 years of ET including tamoxifen and aromatase inhibitor. MD was measured using Cumulus software 4.0 and expressed as a percentage. MD reduction was defined as an absolute difference between the MD of two mammography images: taken preoperatively and 8-20months after the start of adjuvant ET.. Results: After median follow up of 68.8 months, overall recurrence rate was 7.5% (80/1065). Mean MD reduction was 5.9% (-17.2 to 36.9). In a logistic regression analysis, age<50, high preoperative MD, and longer interval between start of ET to the 2nd mammogram were significantly associated with higher MD reduction (p value<0.05). In a survival analysis using Cox model, tumor size (>2cm), lymph node positive, high Ki-67 (≥10%), and lower MD reduction were independent factors significantly associated with recurrence-free survival (p<0.05). The hazard of recurrence increased proportionally according to the less degree of MD reduction. Conclusions: MD change during short-term use of adjuvant ET was a significant predictive factor for long-term recurrence in ER-positive breast cancer. It is urgent to develop effective treatment strategy in patients who have less MD reduction in spite of about 1 year of ET.

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The Central Contributions of Breast Cancer Stem Cells in Developing Resistance to Endocrine Therapy in Estrogen Receptor (ER)-Positive Breast Cancer

Cancers ◽

10.3390/cancers11071028 ◽

2019 ◽

Vol 11 (7) ◽

pp. 1028 ◽

Cited By ~ 19

Author(s):

David Rodriguez ◽

Marc Ramkairsingh ◽

Xiaozeng Lin ◽

Anil Kapoor ◽

Pierre Major ◽

...

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Estrogen Receptor ◽

Cancer Stem Cells ◽

Hormone Therapy ◽

Endocrine Therapy ◽

Endocrine Resistance ◽

Therapy Resistance ◽

Breast Cancer Stem Cells ◽

Er Positive

Breast cancer stem cells (BCSC) play critical roles in the acquisition of resistance to endocrine therapy in estrogen receptor (ER)-positive (ER + ve) breast cancer (BC). The resistance results from complex alterations involving ER, growth factor receptors, NOTCH, Wnt/β-catenin, hedgehog, YAP/TAZ, and the tumor microenvironment. These mechanisms are likely converged on regulating BCSCs, which then drive the development of endocrine therapy resistance. In this regard, hormone therapies enrich BCSCs in ER + ve BCs under both pre-clinical and clinical settings along with upregulation of the core components of “stemness” transcriptional factors including SOX2, NANOG, and OCT4. SOX2 initiates a set of reactions involving SOX9, Wnt, FXY3D, and Src tyrosine kinase; these reactions stimulate BCSCs and contribute to endocrine resistance. The central contributions of BCSCs to endocrine resistance regulated by complex mechanisms offer a unified strategy to counter the resistance. ER + ve BCs constitute approximately 75% of BCs to which hormone therapy is the major therapeutic approach. Likewise, resistance to endocrine therapy remains the major challenge in the management of patients with ER + ve BC. In this review we will discuss evidence supporting a central role of BCSCs in developing endocrine resistance and outline the strategy of targeting BCSCs to reduce hormone therapy resistance.

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