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Glucocorticoid Receptor Activation in Lobular Breast Cancer is Associated with Reduced Cell Proliferation and Promotion of Metastases; SUM44-GR-GFP

ABSTRACT: Estrogen receptor-positive (ER+) invasive lobular breast cancer (ILC) comprises about ~15% of breast cancer. ILC’s unique genotypic (loss of wild type E-cadherin expression) and phenotypic (small individual round cancer cells that grow in discontinuous nests) are thought to contribute to a distinctive pattern of metastases to serosal membranes. Unlike invasive ductal carcinoma (IDC), ILC metastases often intercalate into the mesothelial layer of the peritoneum and other serosal surfaces. While ER activity is a known driver of ILC proliferation, very little is known about how additional nuclear receptors contribute to ILC’s distinctive biology. In ER+ IDC, we showed previously that glucocorticoid receptor (GR) activity inhibits pro-proliferative gene expression and cell proliferation. Here we examined ER+ ILC models and find that GR activation similarly reduces S-phase entry gene expression and ILC proliferation. While slowing tumor growth rate, our data also suggest that GR activation results in an enhanced metastatic phenotype through increasing integrin-encoding gene expression, extracellular matrix protein adhesion, and mesothelial cell clearance. Moreover, in an intraductal mouse mammary gland model of ILC, we found that GR expression is associated with increased metastases despite slowed primary mammary tumor growth. Taken together, our findings suggest GR-mediated gene expression may contribute to the unusual characteristics of ILC biology.

ORGANISM(S): Homo sapiens

PROVIDER: GSE241992 | GEO | 2023/09/04

REPOSITORIES: GEO

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Glucocorticoid Receptor Activation in Lobular Breast Cancer is Associated with Reduced Cell Proliferation and Promotion of Metastases; MM134

Project description:Estrogen receptor-positive (ER+) invasive lobular breast cancer (ILC) comprises about ~15% of breast cancer. ILC’s unique genotypic (loss of wild type E-cadherin expression) and phenotypic (small individual round cancer cells that grow in discontinuous nests) are thought to contribute to a distinctive pattern of metastases to serosal membranes. Unlike invasive ductal carcinoma (IDC), ILC metastases often intercalate into the mesothelial layer of the peritoneum and other serosal surfaces. While ER activity is a known driver of ILC proliferation, very little is known about how additional nuclear receptors contribute to ILC’s distinctive biology. In ER+ IDC, we showed previously that glucocorticoid receptor (GR) activity inhibits pro-proliferative gene expression and cell proliferation. Here we examined ER+ ILC models and find that GR activation similarly reduces S-phase entry gene expression and ILC proliferation. While slowing tumor growth rate, our data also suggest that GR activation results in an enhanced metastatic phenotype through increasing integrin-encoding gene expression, extracellular matrix protein adhesion, and mesothelial cell clearance. Moreover, in an intraductal mouse mammary gland model of ILC, we found that GR expression is associated with increased metastases despite slowed primary mammary tumor growth. Taken together, our findings suggest GR-mediated gene expression may contribute to the unusual characteristics of ILC biology.

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Project description:Invasive lobular cancer (ILC) accounts for approximately 10-15% of breast carcinomas and although it responds poorly to neoadjuvant chemotherapy, it appears to respond well to endocrine therapy. Pre- and on-treatment (after 2 weeks and 3 months) biopsies and surgical samples were obtained from 14 post-menopausal women with ER+ histologically confirmed ILC who responded to 3 months of neoadjuvant letrozole and were compared with a cohort of 14 responding infiltrating ductal carcinomas (IDCs) matched on clinicopathological features by gene expression profiling. Dynamic clinical response was assessed using periodic 3D ultrasound measurements performed during treatment and defined as a reduction of >70% in tumour volume by 3 months. The changes in gene expression in response to letrozole were highly consistent between responding ILC and IDC tumours, genes involved in proliferation were down-regulated and those involved with immune function and ECM remodelling were up-regulated. However, molecular differences between the histological subtypes were maintained upon treatment. This is the first study of molecular changes in ILC in response to endocrine therapy to date. The genes which change on letrozole are highly consistent between ILC and IDC. Differences in gene expression between ILC and IDC at diagnosis and are maintained at each time point on treatment. 14 Pre treatment, 10 two week and 14 three month on-treatment ILC and 14 Pre treatment, 14 two week and 14 three month on-treatment IDC samples from the same patients. Pre- and on-treatment samples from 7ILC & 6IDC patients were profiled on Illumina HT-12v4 (GPL10558) and samples from 7ILC and 8 IDC patients were profiled previously on Affymetrix U133A (GPL96) see GSE20181

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