Dataset Information

Autoantibodies Specific to ER? are Involved in Tamoxifen Resistance in Hormone Receptor Positive Breast Cancer.

ABSTRACT: Tamoxifen resistance is a major hurdle in the treatment of estrogen receptor (ER)-positive breast cancer. The mechanisms of tamoxifen resistance are not fully understood although several underlying molecular events have been suggested. Recently, we identified autoantibodies reacting with membrane-associated ER? (anti-ER? Abs) in sera of breast cancer patients, able to promote tumor growth. Here, we investigated whether anti-ER? Abs purified from sera of ER-positive breast cancer patients could contribute to tamoxifen resistance. Anti-ER? Abs inhibited tamoxifen-mediated effects on cell cycle and proliferation in MCF-7 cells. Moreover, anti-ER? Abs hampered the tamoxifen-mediated reduction of tumor growth in SCID mice xenografted with breast tumor. Notably, simvastatin-mediated disaggregation of lipid rafts, where membrane-associated ER? is embedded, restored tamoxifen sensitivity, preventing anti-ER? Abs effects. In conclusion, detection of serum anti-ER? Abs may help predict tamoxifen resistance and concur to appropriately inform therapeutic decisions concerning hormone therapy in ER-positive breast cancer patients.

SUBMITTER: Maselli A

PROVIDER: S-EPMC6678306 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Autoantibodies Specific to ERα are Involved in Tamoxifen Resistance in Hormone Receptor Positive Breast Cancer.

Maselli Angela A Parlato Stefania S Puglisi Rossella R Raggi Carla C Spada Massimo M Macchia Daniele D Pontecorvi Giada G Iessi Elisabetta E Pagano Maria Teresa MT Cirulli Francesca F Gabriele Lucia L Carè Alessandra A Vici Patrizia P Pizzuti Laura L Barba Maddalena M Matarrese Paola P Pierdominici Marina M Ortona Elena E

Cells 20190719 7

Tamoxifen resistance is a major hurdle in the treatment of estrogen receptor (ER)-positive breast cancer. The mechanisms of tamoxifen resistance are not fully understood although several underlying molecular events have been suggested. Recently, we identified autoantibodies reacting with membrane-associated ERα (anti-ERα Abs) in sera of breast cancer patients, able to promote tumor growth. Here, we investigated whether anti-ERα Abs purified from sera of ER-positive breast cancer patients could c ...[more]

PMID: 31331091

Similar Datasets

Project description:Simple Summary Overexpression of BQ can confer tamoxifen resistance in ER +ve breast cancer. BQ is a variant of NCOR2 spliced through the exclusion of exon 11. SRSF5 is found to be involved in regulating the splicing of NCOR2. A low expression of SRSF5 enhances the chance of excluding exon 11 from mRNA, leading to the production of mRNA translating for BQ. Therefore, a low expression of SRSF5 can enhance BQ expression and, thus, tamoxifen resistance. SRPK1 can alter the activity of SRSF5 for BQ expression. Inhibition of SRPK1 can reduce TAM resistance by suppressing BQ expression in ER +ve breast cancer. Therefore, targeting the upstream pathway of BQ will be a possible strategy for reversing TAM resistance. Abstract About 70% of breast cancer patients are oestrogen receptor-positive (ER +ve). Adjuvant endocrine therapy using tamoxifen (TAM) is an effective approach for preventing local recurrence and metastasis. However, around half of the patients will eventually develop resistance. Overexpression of BQ323636.1 (BQ) is one of the mechanisms that confer TAM resistance. BQ is an alternative splice variant of NCOR2. The inclusion of exon 11 generates mRNA for NCOR2, while the exclusion of exon 11 produces mRNA for BQ. The expression of SRSF5 is low in TAM-resistant breast cancer cells. Modulation of SRSF5 can affect the alternative splicing of NCOR2 to produce BQ. In vitro and in vivo studies confirmed that the knockdown of SRSF5 enhanced BQ expression, and conferred TAM resistance; in contrast, SRSF5 overexpression reduced BQ expression and, thus, reversed TAM resistance. Clinical investigation using a tissue microarray confirmed the inverse correlation of SRSF5 and BQ. Low SRSF5 expression was associated with TAM resistance, local recurrence and metastasis. Survival analyses showed that low SRSF5 expression was associated with poorer prognosis. We showed that SRPK1 can interact with SRSF5 to phosphorylate it. Inhibition of SRPK1 by a small inhibitor, SRPKIN-1, suppressed the phosphorylation of SRSF5. This enhanced the proportion of SRSF5 interacting with exon 11 of NCOR2, reducing the production of BQ mRNA. As expected, SRPKIN-1 reduced TAM resistance. Our study confirms that SRSF5 is essential for BQ expression. Modulating the activity of SRSF5 in ER +ve breast cancer will be a potential approach to combating TAM resistance.

Dataset Information

Autoantibodies Specific to ER? are Involved in Tamoxifen Resistance in Hormone Receptor Positive Breast Cancer.

Publications

Autoantibodies Specific to ERα are Involved in Tamoxifen Resistance in Hormone Receptor Positive Breast Cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets