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A novel bystander effect in tamoxifen treatment: PPIB derived from ER+ cells attenuates ER- cells via endoplasmic reticulum stress-induced apoptosis

ABSTRACT: Tamoxifen (TAM) is the frontline therapy for estrogen receptor-positive (ER+) breast cancer in premenopausal women that interrupts ER signaling. As tumors with elevated heterogeneity, amounts of ER-negative (ER-) cells are present in ER+ breast cancer that cannot be directly killed by TAM. Despite complete remissions have been achieved in clinical practice, the mechanism underlying the elimination of ER- cells during TAM treatment remains an open issue. Herein, we deciphered the elimination of ER- cells in TAM treatment from the perspective of the bystander effect. Markable reductions were observed in tumorigenesis of ER- breast cancer cells by applying both supernatants from TAM-treated ER+ cells and a transwell co-culture system, validating the presence of a TAM-induced bystander effect. The major antitumor protein derived from ER- cells, peptidyl-prolyl cis-trans isomerase B (PPIB), is the mediator of the TAM-induced bystander effect identified by quantitative proteomics. The attenuation of ER- cells was attributed to activated BiP/eIF2α/CHOP axis and promoted endoplasmic reticulum stress (ERS)-induced apoptosis, which can also be triggered by PPIB independently. Altogether, our study revealed a novel TAM-induced bystander effect in TAM treatment of ER+ breast cancer, raising the possibility to develop PPIB as a synergistic antitumor agent or even substitute endocrine therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE247920 | GEO | 2024/02/12

REPOSITORIES: GEO

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Project description:G0/G1 switch gene 2 (G0S2) is known to inhibit lipolysis through inhibition of adipose triglyceride lipase (ATGL). Although G0S2 has also been proposed to be involved in cancer progression, this role appears complex, and mechanisms are unclear. We recently reported a role for G0S2 in ER+ breast cancer suppression as low G0S2 expression correlated with increased recurrence after antiestrogen therapy and increased G0S2 expression sensitized ER+ breast cancer cells to tamoxifen and PI3K/mTOR inhibitors. In this report we dissect the role of G0S2 in ER+ versus ER- breast cancer. Overexpression of G0S2 in ER- breast cancer cells increased cell proliferation while G0S2 overexpression in ER+ breast cancer cells decreased cell proliferation. Transcriptome analysis revealed that G0S2 mediated distinct but overlapping transcriptional responses in ER- and ER+ cells. G0S2 reduced genes associated with an epithelial phenotype, especially in ER- cells, including CDH1, ELF3, STEAP4 and TACSTD2 suggesting promotion of the epithelial-mesenchymal transition (EMT). G0S2 also repressed estrogen signaling and estrogen receptor target gene signatures, especially in ER+ cells, including TFF1 and TFF3. In addition, G0S2 overexpression increased cell migration in ER- cells and increased estrogen deprivation sensitivity in ER+ cells. Interestingly, two genes downstream of ATGL in fat utilization, HMGCS1 and HMGCS2, that are also rate-limiting in steroid hormone biosynthesis, were downregulated in G0S2 overexpressing ER+ cells. In addition, HSD17B11, a gene that converts estradiol to its less estrogenic derivative, estrone, was highly upregulated in G0S2 overexpressing ER+ cells, suggesting G0S2 overexpression has a negative effect of estradiol production and maintenance. High levels of estrone were confirmed to be present in G0S2 overexpressing cells. High expression of G0S2 and HSD17B11 was associated with improved relapse free survival in breast cancer patients while high expression of HMGSC1 was associated with poor survival. In addition, the expression of G0S2 positively and negatively correlated respectively, with expression of HSD17B11 and HMGSC1 in patient samples. Finally, we deleted G0S2 in breast cancer prone MMTV-PyMT mice that have been hypothesized to be partially estrogen sensitive during early stages of tumorigenesis but develop ER- tumors. In this context, G0S2 functioned as a tumor promoter, with G0S2 null mice demonstrating a slight increase in tumor latency and decrease in tumor weight and a larger inhibitory effect on tumor metastasis. Our data indicates a complex role for G0S2 in breast cancer, dependent on ER status, that may be mediated in part by suppression of the estrogen signaling pathway.

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A novel bystander effect in tamoxifen treatment: PPIB derived from ER+ cells attenuates ER- cells via endoplasmic reticulum stress-induced apoptosis

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