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Luminal breast cancer metastasis is dependent on estrogen signaling.

ABSTRACT: Luminal breast cancer is the most frequently encountered type of human breast cancer and accounts for half of all breast cancer deaths due to metastatic disease. We have developed new in vivo models of disseminated human luminal breast cancer that closely mimic the human disease. From initial lesions in the tibia, locoregional metastases develop predictably along the iliac and retroperitoneal lymph node chains. Tumors cells retain their epithelioid phenotype throughout the process of dissemination. In addition, systemically injected metastatic MCF-7 cells consistently give rise to metastases in the skeleton, floor of mouth, adrenal glands, as well as in the lungs, liver, brain and mammary fat pad. We show that growth of luminal breast cancer metastases is highly dependent on estrogen in a dose-dependent manner and that estrogen withdrawal induces rapid growth arrest of metastatic disease. On the other hand, even though micrometastases at secondary sites remain viable in the absence of estrogen, they are dormant and do not progress to macrometastases. Thus, homing to and seeding of secondary sites do not require estrogen. Moreover, in sharp contrast to basal-like breast cancer metastasis in which transforming growth factor-? signaling plays a key role, luminal breast cancer metastasis is independent of this cytokine. These findings have important implications for the development of targeted anti-metastatic therapy for luminal breast cancer.

SUBMITTER: Ganapathy V

PROVIDER: S-EPMC3816364 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Luminal breast cancer metastasis is dependent on estrogen signaling.

Ganapathy Vidya V Banach-Petrosky Whitney W Xie Wen W Kareddula Aparna A Nienhuis Hilde H Miles Gregory G Reiss Michael M

Clinical & experimental metastasis 20120317 5

Luminal breast cancer is the most frequently encountered type of human breast cancer and accounts for half of all breast cancer deaths due to metastatic disease. We have developed new in vivo models of disseminated human luminal breast cancer that closely mimic the human disease. From initial lesions in the tibia, locoregional metastases develop predictably along the iliac and retroperitoneal lymph node chains. Tumors cells retain their epithelioid phenotype throughout the process of disseminati ...[more]

PMID: 22427027

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Project description:Tumors that express estrogen receptor alpha (ER?+) comprise 75% of breast cancers in women. While treatments directed against this receptor have successfully lowered mortality rates, many primary tumors initially or later exhibit resistance. The paucity of murine models of this "luminal" tumor subtype has hindered studies of factors that promote their pathogenesis and modulate responsiveness to estrogen-directed therapeutics. Since epidemiologic studies closely link prolactin and the development of ER?+ tumors in women, we examined characteristics of the aggressive ER?+ and ER?- carcinomas which develop in response to mammary prolactin in a murine transgenic model (neu-related lipocalin- prolactin (NRL-PRL)). To evaluate their relationship to clinical tumors, we determined phenotypic relationships among these carcinomas, other murine models of breast cancer, and features of luminal tumors in women.We examined a panel of prolactin-induced tumors for characteristics relevant to clinical tumors: histotype, ER?/progesterone receptor (PR) expression and estrogen responsiveness, Activating Protein 1 (AP-1) components, and phosphorylation of signal transducer and activator of transcription 5 (Stat5), extracellular signal regulated kinase (ERK) 1/2 and AKT. We compared levels of transcripts in the ER?-associated "luminal" signature that defines this subtype of tumors in women and transcripts enriched in various mammary epithelial lineages to other well-studied genetically modified murine models of breast cancer. Finally, we used microarray analyses to compare prolactin-induced ER?+ and ER?- tumors, and examined responsiveness to estrogen and the anti-estrogen, Faslodex, in vivo.Prolactin-induced carcinomas were markedly diverse with respect to histotype, ER?/PR expression, and activated signaling cascades. They constituted a heterogeneous, but distinct group of murine mammary tumors, with molecular features of the luminal subtype of human breast cancer. In contrast to morphologically normal and hyperplastic structures in NRL-PRL females, carcinomas were insensitive to ER?-mediated signals. These tumors were distinct from mouse mammary tumor virus (MMTV)-neu tumors, and contained elevated transcripts for factors associated with luminal/alveolar expansion and differentiation, suggesting that they arose from physiologic targets of prolactin. These features were shared by ER?+ and ER?- tumors, suggesting a common origin, although the former exhibited transcript profiles reflecting greater differentiation.Our studies demonstrate that prolactin can promote diverse carcinomas in mice, many of which resemble luminal breast cancers, providing a novel experimental model to examine the pathogenesis, progression and treatment responsiveness of this tumor subtype.

Project description:Bypassing estrogen receptor (ER) signaling during development of endocrine resistance remains the most common cause of disease progression and mortality in breast cancer patients. To date, the majority of molecular research on ER action in breast cancer has occurred in cell line models derived from late stage disease. Here we describe patient-derived ER+ luminal breast tumor models for the study of intratumoral hormone and receptor action. Human breast tumor samples obtained from patients post surgery were immediately transplanted into NOD/SCID or NOD/SCID/ILIIrg(-/-) mice under estrogen supplementation. Five transplantable patient-derived ER+ breast cancer xenografts were established, derived from both primary and metastatic cases. These were assessed for estrogen dependency, steroid receptor expression, cancer stem cell content, and endocrine therapy response. Gene expression patterns were determined in select tumors ±estrogen and ±endocrine therapy. Xenografts morphologically resembled the patient tumors of origin, and expressed similar levels of ER (5-99 %), and progesterone and androgen receptors, over multiple passages. Four of the tumor xenografts were estrogen dependent, and tamoxifen or estrogen withdrawal (EWD) treatment abrogated estrogen-dependent growth and/or tumor morphology. Analysis of the ER transcriptome in select tumors revealed notable differences in ER mechanism of action, and downstream activated signaling networks, in addition to identifying a small set of common estrogen-regulated genes. Treatment of a naïve tumor with tamoxifen or EWD showed similar phenotypic responses, but relatively few similarities in estrogen-dependent transcription, and affected signaling pathways. Several core estrogen centric genes were shared with traditional cell line models. However, novel tumor-specific estrogen-regulated potential target genes, such as cancer/testis antigen 45, were uncovered. These results evoke the importance of mapping both conserved and tumor-unique ER programs in breast cancers. Furthermore, they underscore the importance of primary xenografts for improved understanding of ER+ breast cancer heterogeneity and development of personalized therapies.

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Luminal breast cancer metastasis is dependent on estrogen signaling.

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Luminal breast cancer metastasis is dependent on estrogen signaling.

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