Abstract
PurposeOverexpression of breast cancer (BCa) resistance protein (BCRP) is detected in approximately 30% of BCa cases. BCRP indicates a poor response to chemotherapy, and it has become a classic target to overcome drug-resistant tumor cells. In this study, we aimed to explore the mechanism of BCRP overexpression and a strategy to reverse this overexpression in invasive BCa.MethodsBCRP expression in BCa tissues was determined by immunohistochemistry. GSE25066 was downloaded from the NCBI GEO database. Western blot was used to determine the expression of key molecules in vitro. Cell counting kit-8 assays were used to assess the drug response of BCa cells.ResultsOur results suggested that BCRP is an independent risk factor for BCa. We further established that upon 17α-PG binding, membrane progesterone receptor α (mPRα) promoted BCRP expression via the PI3K/Akt/mTOR signaling pathway. mPRα physically interacted with p-Akt1 S473. Moreover, rapamycin, an inhibitor of mTOR complex 1 (mTORC1), downregulated BCRP expression and enhanced the effects of particular drugs, including doxorubicin and paclitaxel.ConclusionBCRP is a potential biomarker of poor prognosis in BCa. BCRP expression is regulated by 17α-PG in mPRα-positive BCa cells through the PI3K/Akt/mTOR signaling pathway. Rapamycin might enhance the therapeutic effect of chemotherapy agents in mPRα-positive MDA-MB-453/BCRP cells and might be a therapeutic option for mPRα-positive invasive BCa with BCRP overexpression.
Highlights
Chemotherapy is considered to be a vital treatment strategy in invasive breast cancer (BCa)
We previously reported a positive correlation between mPRa protein expression and lymph node metastasis, suggesting that mPRa is a potential mediator of invasive BCa progression
BCa resistance protein (BCRP) expression in primary BCa was evaluated by IHC
Summary
Chemotherapy is considered to be a vital treatment strategy in invasive breast cancer (BCa). BCRP plays a critical role in BCa drug resistance by increasing the cellular excretion of chemotherapeutics [1,2,3]. Female sex hormones play key roles in the pathogenesis of BCa. We have reported that progesterone receptor (PR) and estrogen receptor a (ERa) modulate the expression of BCRP, and overexpression of BCRP promotes BCa metastasis [4]. We have reported that progesterone receptor (PR) and estrogen receptor a (ERa) modulate the expression of BCRP, and overexpression of BCRP promotes BCa metastasis [4] This phenomenon partially depends on the classic genomic pathway of steroid nuclear receptor signaling. All types of steroid hormones have been reported to have rapid, nongenomic effects that occur at the cell membrane or mitochondria [5]. Steroid hormone receptors interact with multiple signaling molecules modeling their activation state
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