Molecular Changes in Lobular Breast Cancers in Response to Endocrine Therapy

Abstract

Invasive lobular carcinoma (ILC) accounts for approximately 10% to 15% of breast carcinomas, and although it responds poorly to neoadjuvant chemotherapy, it appears to respond well to endocrine therapy. Pre-and ontreatment (after 2 weeks and 3 months) biopsies and surgical samples were obtained from 14 postmenopausal women with estrogen receptor-positive (ER þ ) histologically confirmed ILC who responded to 3 months of neoadjuvant letrozole and were compared with a cohort of 14 responding invasive ductal carcinomas (IDC) matched on clinicopathologic features. RNA was extracted and processed for whole human genome expression microarray. Dynamic clinical response was assessed using periodic three-dimensional ultrasound measurements performed during treatment and defined as a reduction of >70% in tumor volume by 3 months. Pretreatment profiles of ILC and IDC tumors showed distinctive expression of genes associated with E-cadherin signaling, epithelial adhesion, and stromal rearrangement. The changes in gene expression in response to letrozole were highly similar between responding ILC and IDC tumors; genes involved in proliferation were downregulated and those involved with immune function and extracellular matrix remodeling were upregulated. However, molecular differences between the histologic subtypes were maintained upon treatment. This is the first study of molecular changes in ILC in response to endocrine therapy to date. The genes that change on letrozole are highly consistent between ILC and IDC. Differences in gene expression between ILC and IDC at diagnosis are maintained at each time point on treatment. Cancer Res; 74(19);

Key regulators of lipid metabolism drive endocrine resistance in invasive lobular breast cancer

“…Currently, there are no gene expression data available from a neoadjuvant trial with sufficiently large numbers of patients with ILC and treatment response data (for example, Ki67) to perform such analyses. An elegant study by Arthur et al [69] analyzed gene expression in ILC compared with IDC tumors in the neoadjuvant setting; however, the study was limited to responders and thus does not allow comparison of SREBP levels between sensitive and resistant tumors. Finally, our cell line studies were limited to in vitro studies at this point in time, and future studies should include mouse models, which would further solidify our findings.…”

Single cell transcriptomic heterogeneity in invasive ductal and lobular breast cancer cells

“…In breast cancer, IRF1 depletion could well indicate endocrine resistance, while its induction by IFNg sensitize cancer cells to endocrine therapy 40 . These traits conform to multiple ILC phenotypes compared to IDC, e.g., being less proliferative and more apoptotic 41,42 ; and showing a better response to as well as a better outcome upon adjuvant endocrine therapy 43,44 . Specifically, IRF1 mediates antiestrogen-induced apoptosis, by increasing expression of pro-apoptotic genes (BAK, BAX, BIK) while reducing that of anti-apoptotic genes (BCL2, BCLW, survivin) 45 .…”

Molecular changes during extended neoadjuvant letrozole treatment of breast cancer: distinguishing acquired resistance from dormant tumours

“…RNA was extracted from the aqueous phase by column-based purification (RNeasy mini kit, Qiagen) and then labelled and hybridized (HumanHT-12 v4 Illumina BeadChip) according to manufacturer’s protocol (NuGEN) as previously described [19, 20]. Raw data was detection ( p < 0.05, ≥ 3 samples) and quality filtered, log2 transformed, and quantile normalized using the Bioconductor lumi package [21].…”

“…Data is available from NCBI GEO under accession GSE111563. The analysis also includes data from 14 patients (42 samples, GSE59515) and 9 patients (24 samples, GSE55374) from previous studies [16, 19]. Hierarchical clustering analysis was performed using a complete linkage method.…”