The high expression of <scp>FOXA</scp>1 is correlated with a favourable prognosis in salivary duct carcinomas: a study of 142 cases

Urano, Makoto; Hirai, Hideaki; Tada, Yuichiro; Kawakita, Daisuke; Shimura, Tomotaka; Tsukahara, Kiyoaki; Kano, Satoshi; Ozawa, Hiroyuki; Okami, Kenji; Sato, Yuichiro; Fushimi, Chihiro; Shimizu, Akira; Takase, Soichiro; Okada, Takenori; Sato, Hiroki; Imanishi, Yorihisa; Otsuka, Kenju; Watanabe, Yoshihiro; Sakai, Akihiro; Ebisumoto, Koji; Togashi, Takafumi; Ueki, Yushi; Ota, Hisayuki; Sato, Yukiko; Saigusa, Naoto; Nakaguro, Masato; Hanazawa, Toyoyuki; Nagao, Toshitaka

doi:10.1111/his.13706

Cited by 11 publications

(14 citation statements)

References 58 publications

(205 reference statements)

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“…The association between the expression of FASN and FOXA1 in cancer has not been examined. In SDC, the FOXA1 expression was positively correlated with the expression of AR [4]; thus, there might be a positive relationship between FASN and FOXA1. Recently, therapies targeting AR have been shown to be effective in SDC patients and have attracted attention [32].…”

Section: Discussionmentioning

confidence: 97%

“…Ki-67 LI values of < 40% and ≥ 40% were classified as Ki-67-low and Ki-67-high, respectively [9]. The HER2 status and the results of immunohistochemical staining of AR, FOXA1, Ki-67, and p53, which were previously reported by our group, were compared to the ADP and FASN expression [4,27,29].…”

Section: Immunohistochemistry (Ihc) and Fluorescence In Situ Hybridizmentioning

confidence: 99%

“…The association between the ADP expression and overall survival (OS) or progression-free survival (PFS) was evaluated using the Kaplan-Meier product-limit method and univariate and multivariate Cox proportional hazard models. The potential confounders in the multivariate analysis included the age (< 65 vs. ≥ 65 years), sex (male vs. female), primary tumor site (parotid gland vs. submandibular gland vs. other), T classification (1)(2)(3)(4), N classification (0 vs. 1, 2), M classification (0, 1), first-line treatment (surgery vs. other), and histological type (de novo vs. carcinoma ex pleomorphic adenoma). All statistical tests were performed using the STATA software program (version 13, StataCorp, College Station, TX, USA).…”

Section: Statistical Analysesmentioning

confidence: 99%

“…SDC is histologically comparable to high-grade mammary ductal carcinoma and recent transcriptome data have also shown striking similarities between SDC and apocrine breast cancer [2]. Most SDCs express androgen receptor (AR) and its related protein, FOXA1, but not estrogen receptor (ER) or progesterone receptor, and approximately 40% are positive for HER2 [3,4].…”

Section: Introductionmentioning

confidence: 99%

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The clinicopathological significance of the adipophilin and fatty acid synthase expression in salivary duct carcinoma

et al. 2020

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Salivary duct carcinoma (SDC) is an aggressive, uncommon tumor histologically comparable to high-grade mammary ductal carcinoma. SDCs are usually androgen receptor (AR)-positive and often HER2-positive. Recently, therapies targeting these molecules for SDC have attracted attention. Lipid metabolism changes have been described in association with biological behavior in various cancers, although no such relationship has yet been reported for SDC. We therefore analyzed the clinicopathological relevance of the immunohistochemical expression of adipophilin (ADP) and fatty acid synthase (FASN), representative lipid metabolism-related proteins, in 147 SDCs. ADP and FASN were variably immunoreactive in most SDCs (both 99.3%), and the ADP and FASN expression was negatively correlated (P = 0.014). ADPpositive (≥ 5%) SDCs more frequently exhibited a prominent nuclear pleomorphism and high-Ki-67 labeling index than those ADP-negative (P = 0.013 and 0.011, respectively). In contrast, a high FASN score, calculated by the staining proportion and intensity, (≥ 120) was correlated with the high expression of AR and FOXA1 (P < 0.001 and = 0.003, respectively). The ADP and FASN expression differed significantly among the subtypes based on biomarker immunoprofiling, as assessed by the AR, HER2, and Ki-67 status (P = 0.017 and 0.003, respectively). A multivariate analysis showed that ADP-positive expression was associated with a shorter overall and progression-free survival (P = 0.018 and 0.003, respectively). ADP was associated with an aggressive histopathology and unfavorable prognosis, and FASN may biologically interact with the AR signaling pathway in SDC. ADP may, therefore, be a new prognostic indicator and therapeutic target in SDC.

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Section: Discussionmentioning

confidence: 97%

Section: Immunohistochemistry (Ihc) and Fluorescence In Situ Hybridizmentioning

confidence: 99%

Section: Statistical Analysesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The clinicopathological significance of the adipophilin and fatty acid synthase expression in salivary duct carcinoma

et al. 2020

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“…Thus, Foxa1 is a promising target gene of AR signaling in duct development. Mutations in the FOXA1 gene are also associated with the prognosis of human salivary duct carcinoma (Urano et al, 2018), breast cancer (Rangel et al, 2018;Robinson and Carroll, 2012) and prostate cancer (Robinson and Carroll, 2012).…”

Section: Discussionmentioning

confidence: 99%

Cholesterol metabolism plays a crucial role in the regulation of autophagy for cell differentiation of granular convoluted tubules in male mouse submandibular glands

et al. 2019

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It has been long appreciated that sex hormone receptors are expressed in various non-gonadal organs. However, it remains unclear how sex hormones regulate the morphogenesis of these nongonadal organs. To address this issue, we used a male mouse model of androgen-dependent salivary gland morphogenesis. Mice with excessive cholesterol synthesis in the salivary glands exhibited defects in the maturation of granular convoluted tubules (GCTs), which is regulated through sex hormone-dependent cascades. We found that excessive cholesterol synthesis resulted in autophagy failure specifically in the duct cells of salivary glands, followed by the accumulation of NRF2, a transcription factor known as one of the specific substrates for autophagy. The accumulated NRF2 suppressed the expression of Foxa1, which forms a transcriptional complex with the androgen receptor to regulate target genes. Taken together, our results indicate that cholesterol metabolism plays a crucial role in GCT differentiation through autophagy.

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Salivary duct carcinoma: Updates in histology, cytology, molecular biology, and treatment

Nakaguro

Tada

Faquin

et al. 2020

Cancer Cytopathology

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Salivary duct carcinoma (SDC) is an aggressive subtype of primary salivary gland carcinoma, often with an advanced stage at presentation and high rates of metastasis and recurrence. It most commonly arises in the parotid gland of older men and microscopically resembles high-grade breast ductal carcinoma. While 50 years have lapsed since the first report of this entity, recent intensive studies have shed light on its biologic, genetic, and clinical characteristics. The diagnosis of SDC is aided by the immunohistochemical expression of androgen receptor (AR) coupled with its characteristic histomorphology. Fine-needle aspiration typically reveals cytologic features of high-grade carcinoma, and ancillary studies using cell block material can facilitate the specific diagnosis of SDC. In surgical specimens, certain histologic features are important prognostic factors, including nuclear pleomorphism, mitotic counts, vascular invasion, and the morphology at the invasion front. Several clinical studies have shown promising results using targeted therapy for AR and human epidermal growth factor receptor 2 (HER2), and the latest version of the National Comprehensive Cancer Network guidelines recommends the evaluation of AR and HER2 status before treatment. Recent molecular analyses have revealed multiple heterogeneous alterations in wellknown oncogenes and tumor suppressor genes, including TP53, HRAS, PIK3CA, PTEN, and BRAF. Clinical trials of drugs targeting these genes may broaden the treatment options for SDC in the near future.

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The high expression of FOXA1 is correlated with a favourable prognosis in salivary duct carcinomas: a study of 142 cases

Abstract: In SDC, FOXA1, which may biologically interact with the AR and PI3K signalling pathways, is a putative biomarker that may be associated with a favourable prognosis. Further studies are needed to apply the findings to the development of targeted personalised therapy for patients with SDC.

Cited by 11 publications

References 58 publications

The clinicopathological significance of the adipophilin and fatty acid synthase expression in salivary duct carcinoma

The clinicopathological significance of the adipophilin and fatty acid synthase expression in salivary duct carcinoma

Cholesterol metabolism plays a crucial role in the regulation of autophagy for cell differentiation of granular convoluted tubules in male mouse submandibular glands

Salivary duct carcinoma: Updates in histology, cytology, molecular biology, and treatment

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