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GPR110 promotes progression and metastasis of triple-negative breast cancer.

ABSTRACT: Breast cancer is the most common type of cancer in women, and approximately 70% of all breast cancer patients use endocrine therapy, such as estrogen receptor modulators and aromatase inhibitors. In particular, triple-negative breast cancer (TNBC) remains a major threat due to the lack of targeted treatment options and poor clinical outcomes. Here, we found that GPR110 was highly expressed in TNBC and GPR110 plays a key role in TNBC progression by engaging the RAS signaling pathway (via Gαs activation). High expression of GPR110 promoted EMT and CSC phenotypes in breast cancer. Consequently, our study highlights the critical role of GPR110 as a therapeutic target and inhibition of GPR110 could provide a therapeutic strategy for the treatment of TNBC patients.

SUBMITTER: Nam HJ

PROVIDER: S-EPMC9132940 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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GPR110 promotes progression and metastasis of triple-negative breast cancer.

Nam Hye-Jung HJ Kim Yeon-Ju YJ Kang Jae-Hyeok JH Lee Su-Jae SJ

Cell death discovery 20220526 1

Breast cancer is the most common type of cancer in women, and approximately 70% of all breast cancer patients use endocrine therapy, such as estrogen receptor modulators and aromatase inhibitors. In particular, triple-negative breast cancer (TNBC) remains a major threat due to the lack of targeted treatment options and poor clinical outcomes. Here, we found that GPR110 was highly expressed in TNBC and GPR110 plays a key role in TNBC progression by engaging the RAS signaling pathway (via Gαs acti ...[more]

PMID: 35614051

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Project description:BackgroundCyclin-dependent kinase 16 (CDK16) is an atypical PCTAIRE kinase, and its activity is dependent on the Cyclin Y (CCNY) family. Ccnys have been reported to regulate mammary stem cell activity and mammary gland development, and CCNY has been recognized as an oncoprotein in various cancers, including breast cancer. However, it remains unclear whether CDK16 has a role in breast cancer and whether it can be used as a therapeutic target for breast cancer.MethodsPublicly available breast cancer datasets analyses and Kaplan-Meier survival analyses were performed to reveal the expression and clinical relevance of atypical CDKs in breast cancer. CDK16 protein expression was further examined by immunohistochemical and immunoblot analyses of clinical samples. Cell proliferation was measured by colony formation and MTT analyses. Cell cycle and apoptosis were examined by fluorescence-activated cell sorting (FACS) analysis. Wound-healing and trans-well invasion assays were conducted to test cell migration ability. The functions of CDK16 on tumorigenesis and metastasis were evaluated by cell line-derived xenograft, patient-derived organoid/xenograft, lung metastasis and systemic metastasis mouse models. Transcriptomic analysis was performed to reveal the potential molecular mechanisms involved in the function of CDK16. Pharmacological inhibition of CDK16 was achieved by the small molecular inhibitor rebastinib to further assess the anti-tumor utility of targeting CDK16.ResultsCDK16 is highly expressed in breast cancer, particularly in triple-negative breast cancer (TNBC). The elevated CDK16 expression is correlated with poor outcomes in breast cancer patients. CDK16 can improve the proliferation and migration ability of TNBC cells in vitro, and promote tumor growth and metastasis of TNBC in vivo. Both genetic knockdown and pharmacological inhibition of CDK16 significantly suppress the tumor progression of TNBC. Mechanistically, CDK16 exerts its function by phosphorylating protein regulator of cytokinesis 1 (PRC1) to regulate spindle formation during mitosis.ConclusionCDK16 plays a critical role in TNBC and is a novel promising therapeutic target for TNBC.

Project description:BackgroundBreast cancer (BC) is the most common cancer in women and the leading cause of cancer-associated mortality in women. In particular, triple-negative BC (TNBC) has the highest rate of mortality due in large part to the lack of targeted treatment options for this subtype. Thus, there is an urgent need to identify new molecular targets for TNBC treatment. RALA and RALB are small GTPases implicated in growth and metastasis of a variety of cancers, although little is known of their roles in BC.MethodsThe necessity of RALA and RALB for TNBC tumor growth and metastasis were evaluated in vivo using orthotopic and tail-vein models. In vitro, 2D and 3D cell culture methods were used to evaluate the contributions of RALA and RALB during TNBC cell migration, invasion, and viability. The association between TNBC patient outcome and RALA and RALB expression was examined using publicly available gene expression data and patient tissue microarrays. Finally, small molecule inhibition of RALA and RALB was evaluated as a potential treatment strategy for TNBC in cell line and patient-derived xenograft (PDX) models.ResultsKnockout or depletion of RALA inhibited orthotopic primary tumor growth, spontaneous metastasis, and experimental metastasis of TNBC cells in vivo. Conversely, knockout of RALB increased TNBC growth and metastasis. In vitro, RALA and RALB had antagonistic effects on TNBC migration, invasion, and viability with RALA generally supporting and RALB opposing these processes. In BC patient populations, elevated RALA but not RALB expression is significantly associated with poor outcome across all BC subtypes and specifically within TNBC patient cohorts. Immunohistochemical staining for RALA in patient cohorts confirmed the prognostic significance of RALA within the general BC population and the TNBC population specifically. BQU57, a small molecule inhibitor of RALA and RALB, decreased TNBC cell line viability, sensitized cells to paclitaxel in vitro and decreased tumor growth and metastasis in TNBC cell line and PDX models in vivo.ConclusionsTogether, these data demonstrate important but paradoxical roles for RALA and RALB in the pathogenesis of TNBC and advocate further investigation of RALA as a target for the precise treatment of metastatic TNBC.

Project description:Triple-negative breast cancer (TNBC) is a distinct breast cancer subtype defined by the absence of estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2/neu), and the patients with TNBC are often diagnosed with higher rates of recurrence and metastasis. Because of the absence of ER, PR and HER2/neu expressions, TNBC patients are insensitive to HER2-directed and endocrine therapies available for breast cancer treatment. Here, we report that expression of atypical protein kinase C isoform, PKCλ/ι, significantly increased and activated in all invasive breast cancer (invasive ductal carcinoma or IDC) subtypes including the TNBC subtype. Because of the lack of targeted therapies for TNBC, we choose to study PKCλ/ι signaling as a potential therapeutic target for TNBC. Our observations indicated that PKCλ/ι signaling is highly active during breast cancer invasive progression, and metastatic breast cancers, the advanced stages of breast cancer disease that developed more frequently in TNBC patients, are also characterized with high levels of PKCλ/ι expression and activation. Functional analysis in experimental mouse models revealed that depletion of PKCλ/ι significantly reduces TNBC growth as well as lung metastatic colonization. Furthermore, we have identified a PKCλ/ι-regulated gene signature consisting of 110 genes, which are significantly associated with indolent to invasive progression of human breast cancer and poor prognosis. Mechanistically, cytokines such as TGFβ and IL1β could activate PKCλ/ι signaling in TNBC cells and depletion of PKCλ/ι impairs NF-κB p65 (RelA) nuclear localization. We observed that cytokine-PKCλ/ι-RelA signaling axis, at least in part, involved in modulating gene expression to regulate invasion of TNBC cells. Overall, our results indicate that induction and activation of PKCλ/ι promote TNBC growth, invasion and metastasis. Thus, targeting PKCλ/ι signaling could be a therapeutic option for breast cancer, including the TNBC subtype.

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GPR110 promotes progression and metastasis of triple-negative breast cancer.

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GPR110 promotes progression and metastasis of triple-negative breast cancer.

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