Raptor localization predicts prognosis and tamoxifen response in estrogen receptor-positive breast cancer

Abstract

PurposeDeregulated PI3K/mTOR signals can promote the growth of breast cancer and contribute to endocrine treatment resistance. This report aims to investigate raptor and its intracellular localization to further understand its role in ER-positive breast cancer.MethodsRaptor protein expression was evaluated by immunohistochemistry in 756 primary breast tumors from postmenopausal patients randomized to tamoxifen or no tamoxifen. In vitro, the MCF7 breast cancer cell line and tamoxifen-resistant MCF7 cells were studied to track the raptor signaling changes upon resistance, and raptor localization in ERα-positive cell lines was compared with that in ERα-negative cell lines.ResultsRaptor protein expression in the nucleus was high in ER/PgR-positive and HER2-negative tumors with low grade, features associated with the luminal A subtype. Presence of raptor in the nucleus was connected with ERα signaling, here shown by a coupled increase of ERα phosphorylation at S167 and S305 with accumulation of nuclear raptor. In addition, the expression of ERα-activated gene products correlated with nuclear raptor. Similarly, in vitro we observed raptor in the nucleus of ERα-positive, but not of ER-negative cells. Interestingly, raptor localized to the nucleus could still be seen in tamoxifen-resistant MCF7 cells. The clinical benefit from tamoxifen was inversely associated with an increase of nuclear raptor. High cytoplasmic raptor expression indicated worse prognosis on long-term follow-up.ConclusionWe present a connection between raptor localization to the nucleus and ERα-positive breast cancer, suggesting raptor as a player in stimulating the growth of the luminal A subtype and a possible target along with endocrine treatment.Electronic supplementary materialThe online version of this article (10.1007/s10549-017-4508-x) contains supplementary material, which is available to authorized users.

Genomic and molecular features distinguish young adult cancer from later-onset cancer

“…RPTOR amplification was specifically enriched in basal and luminal A BRCA in young adults ( Figure 2D ). Recent studies have linked RPTOR activity with treatment implications in triple-negative and luminal-A breast cancer models ( Bostner et al, 2018 ; You et al, 2018 ). More, the druggable ERBB2 amplification occurred in a quarter of young adult breast cancer cases.…”

PI3K/AKT/mTOR Signaling Pathway in Breast Cancer: From Molecular Landscape to Clinical Aspects

“…Bostner J and co-workers detected that raptor protein expression in the nucleus was increased in ER/PgR-positive and HER2-negative tumors with low grade, further associated with the luminal A subtype. Moreover, raptor seems to stimulate the growth of the luminal A subtype and may be a possible target along with endocrine treatment [ 196 ]. Zhu L et al, treated human breast cancer cell lines (MCF-7 and ZR-75–1) with tamoxifen or rapamycin, to observe if ER positive breast cancer cell growth is inhibited.…”

Lifetime Impact of Cow’s Milk on Overactivation of mTORC1: From Fetal to Childhood Overgrowth, Acne, Diabetes, Cancers, and Neurodegeneration

“…In addition, nuclear mTOR kinase phosphorylates ERα on S104/106 and thereby activates transcription of ER target genes [ 373 ]. Upon mitogen and estrogen stimulation, S6K1 and mTORC1, respectively, are able to phosphorylate ERα, significantly affecting chromatin binding and transcriptional activity in a ligand independent fashion [ 373 , 374 , 375 , 376 ], while establishing a feed-forward mechanism that may drive cancer progression through upregulation of eIF3 by ERα [ 377 , 378 ].…”