The challenges of modeling hormone receptor-positive breast cancer in mice

Abstract

Estrogen receptor-positive (ER+) tumors account for 70-80% of all breast cancer (BC) cases and are characterized by estrogen dependency for their growth. Endocrine therapies using estrogen receptor antagonists or aromatase inhibitors represent a key component of the standard of care for these tumors. The occurrence of de novo or acquired resistance to estrogen withdrawal represents an important clinical problem, impacting on patient survival. In addition, despite an initially favorable outcome, a part of ER+ BC patients present with disease recurrence locally or at distant sites years or even decades after apparent remission. models that closely mimic human disease are urgently needed to study the biology of these tumors, investigate the molecular mechanisms underlying endocrine resistance and identify patients at risk of recurrence. Despite the similarities in the overall hormonal regulation of mammary gland development between mice and humans, the majority of the mammary carcinomas occurring in genetically engineered mouse models (GEMMs) are ER negative and most xenograft models are based on few ER+ cancer cell lines. We recently showed that the microenvironment is critical for ER+ cancer cells and discuss in this review the potential of intraductal xenograft model for basic and preclinical research.

Progesterone promotes immunomodulation and tumor development in the murine mammary gland

“…Assessment of tumor histology was performed following (H&E) staining, which revealed the majority of the tumors were adenocarcinomas with squamous metaplasia ( online supplemental table 2 ). Interestingly, as is the case with the majority of murine mammary gland models, 76 all tumors in both groups were ER-negative/PR-negative (by IHC and RT-qPCR, data not shown), despite arising from a majority-PR+ mammary gland (see figure 1B ). In order to molecularly classify the tumors that developed in the PR/Gal4 mice versus controls, we performed RNA-Seq on tumor RNA isolated at the time of sacrifice.…”

“…Surprisingly, despite arising from mammary glands with transgenic PR overexpression reaching nearly 80%, the tumors that developed in the PR/Gal4 mice (and Gal4 controls) are ER/PR-negative tumors. Although the majority of spontaneous tumor models in mice are ER/PR-negative, 76 it raises interesting questions about what role PR plays in driving increased tumor incidence in this mouse model. First, the immune-related gene signature differences between the PR/Gal4 and Gal4 tumors suggest that PR expression in the transgenic mammary gland serves to remodel the immune system to support tumor development, more so than to drive oncogenic events within the tumor cell.…”

Characterization of circulating breast cancer cells with tumorigenic and metastatic capacity

“…To assess tumorigenic as well as metastatic potential of the CTC‐ITB‐01 line, a GFP‐luciferase transduced cell population was directly injected into the mouse milk duct system of four 10‐week‐old immunodeficient NOD scid gamma (NSG) females. This has proven to be an efficient model for ER + cancer cell lines, allowing outgrowth under physiological systemic estrogen and low SLUG levels (Sflomos et al , ; Ozdemir et al , ). Mice were monitored by in vivo bioluminescence imaging to assess the formation and proliferation of primary tumors and spontaneous metastases in clinical relevant tissues.…”

MAM domain containing 2 is a potential breast cancer biomarker that exhibits tumour‐suppressive activity

“…Although different studies classify breast cancer cell lines into different categories, the most general subtyping is based on the expression of three immunohistochemistry markers, ER, progesterone receptor (PR) and the human epidermal growth factor receptor 2 (HER2) 15 . Although ER‐positive tumours are very common, accounting for 70 to 80% of all breast cancer cases, only about 30% of cell lines are ER+, because ER‐negative cells are more likely to be established 16 . Despites the broad phenotypic spectrum of breast cancers, three cell lines (MCF7, T‐47D and MDA‐MB‐231) account for more than two‐thirds of breast cancer studies 14 .…”