Molecular-level analyses of breast carcinogenesis benefit from vivo disease models. Estrogen receptor 1 (Esr1) and cytochrome P450 family 19 subfamily A member 1 (CYP19A1) overexpression targeted to mammary epithelial cells in genetically engineered mouse
models induces largely similar rates of proliferative mammary disease in prereproductive
senescent mice. Herein, with natural reproductive senescence, Esr1 overexpression compared with CYP19A1 overexpression resulted in significantly higher rates of preneoplasia and cancer.
Before reproductive senescence, Esr1, but not CYP19A1, overexpressing mice are tamoxifen resistant. However, during reproductive senescence,
Esr1 mice exhibited responsiveness. Both Esr1 and CYP19A1 are responsive to letrozole before and after reproductive senescence. Gene Set Enrichment
Analyses of RNA-sequencing data sets showed that higher disease rates in Esr1 mice were accompanied by significantly higher expression of cell proliferation genes,
including members of prognostic platforms for women with early-stage hormone receptor–positive
disease. Tamoxifen and letrozole exposure induced down-regulation of these genes and
resolved differences between the two models. Both Esr1 and CYP19A1 overexpression induced abnormal developmental patterns of pregnancy-like gene expression.
This resolved with progression through reproductive senescence in CYP19A1 mice, but was more persistent in Esr1 mice, resolving only with tamoxifen and letrozole exposure. In summary, genetically
engineered mouse models of Esr1 and CYP19A1 overexpression revealed a diversion of disease processes resulting from the two distinct
molecular pathophysiological mammary gland–targeted intrusions into estrogen signaling
during reproductive senescence.
Graphical abstract
Graphical Abstract
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References
- Global challenges and policy solutions in breast cancer control.Cancer Treat Rev. 2022; 104: 102339
- Targeting the cell cycle in breast cancer: towards the next phase.Cell Cycle. 2018; 17: 1871-1885
- Natural and synthetic estrogens in chronic inflammation and breast cancer.Cancers (Basel). 2021; 14: 206
- Endogenous and therapeutic estrogens: maestro conductors of the microenvironment of ER+ breast cancers.Cancers (Basel). 2021; 13: 3725
- The aged breast.J Pathol. 2007; 211: 232-240
- Menopause is a determinant of breast aromatase expression and its associations with BMI, inflammation, and systemic markers.J Clin Endocrinol Metab. 2017; 102: 1692-1701
- Estrogen receptor-[alpha] signaling in post-natal mammary development and breast cancers.Cell Mol Life Sci. 2021; 78: 5681-5705
- Estrogen and antiestrogen regulation of cell cycle progression in breast cancer cells.Endocr Relat Cancer. 2003; 10: 179-186
- Links between oestrogen receptor activation and proteolysis: relevance to hormone-regulated cancer therapy.Nat Rev Cancer. 2014; 14: 26-38
- Estrogen signaling via a linear pathway involving insulin-like growth factor I receptor, matrix metalloproteinases, and epidermal growth factor receptor to activate mitogen-activated protein kinase in MCF-7 breast cancer cells.Endocrinology. 2007; 148: 4091-4101
- Mechanistic effects of estrogens on breast cancer.Cancer J. 2022; 28: 224-240
- Aromatase expression and regulation in breast and endometrial cancer.J Mol Endocrinol. 2016; 57: R19-R33
- Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial.Lancet Oncol. 2015; 16: 67-75
- The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial.JAMA. 1999; 281: 2189-2197
- Exemestane for breast-cancer prevention in postmenopausal women.N Engl J Med. 2011; 364: 2381-2391
- Aromatase inhibitors in breast cancer prevention.Ann Pharmacother. 2014; 48: 1605-1610
- Breast cancer prevention by antihormones and other drugs: where do we stand?.Hematol Oncol Clin North Am. 2013; 27: 657-672
- Interferon signaling in estrogen receptor–positive breast cancer: a revitalized topic.Endocrinology. 2022; 163: bqab235
- Comparison of tamoxifen and letrozole response in mammary preneoplasia of ER and aromatase overexpressing mice defines an immune-associated gene signature linked to tamoxifen resistance.Carcinogenesis. 2015; 36: 122-132
- The role of interferon regulatory factor-1 (IRF1) in overcoming antiestrogen resistance in the treatment of breast cancer.Int J Breast Cancer. 2011; 2011: 912102
- Targeting interferon response genes sensitizes aromatase inhibitor resistant breast cancer cells to estrogen-induced cell death.Breast Cancer Res. 2015; 17: 6
- An update on breast cancer multigene prognostic tests—emergent clinical biomarkers.Front Med (Lausanne). 2018; 5: 248
- A narrative review of five multigenetic assays in breast cancer.Transl Cancer Res. 2022; 11: 897-907
- Prognostic significance of different molecular typing methods and immune status based on RNA sequencing in HR-positive and HER2-negative early-stage breast cancer.BMC Cancer. 2022; 22: 548
- PAM50 risk of recurrence score predicts 10-year distant recurrence in a comprehensive Danish cohort of postmenopausal women allocated to 5 years of endocrine therapy for hormone receptor–positive early breast cancer.J Clin Oncol. 2018; 36: 735-740
- Predicting breast cancer risk using interacting genetic and demographic factors and machine learning.Sci Rep. 2020; 10: 11044
- Clinical treatment score post-5 years as a predictor of late distant recurrence in hormone receptor-positive breast cancer: systematic review and meta-analysis.Br J Surg. 2022; 109: 411-417
- Characterization of transcriptome diversity and in vitro behavior of primary human high-risk breast cells.Sci Rep. 2022; 12: 6159
- Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors.Genome Biol. 2007; 8: R76
- Initiating oncogenic event determines gene-expression patterns of human breast cancer models.Proc Natl Acad Sci U S A. 2002; 99: 6967-6972
- Assessing estrogen signaling aberrations in breast cancer risk using genetically engineered mouse models.Ann N Y Acad Sci. 2011; 1229: 147-155
- Genetically engineered ER[alpha]-positive breast cancer mouse models.Endocr Relat Cancer. 2014; 21: R195-R208
- Transgenic mouse models of hormonal mammary carcinogenesis: advantages and limitations.Steroid Biochem Mol Biol. 2012; 131: 76-82
- Comparison of increased aromatase versus ER[alpha] in the generation of mammary hyperplasia and cancer.Cancer Res. 2011; 71: 5477-5487
- Association of over-expressed estrogen receptor alpha with development of tamoxifen resistant hyperplasia and adenocarcinomas in genetically engineered mice.Anat Physiol. 2012; : 001
- Role of ER[alpha] in the differential response of Stat5a loss in susceptibility to mammary preneoplasia and DMBA-induced carcinogenesis.Carcinogenesis. 2010; 31: 1124-1131
- Keratins in health and cancer: more than mere epithelial cell markers.Oncogene. 2011; 30: 127-138
- Keratin expression in breast cancers.Virchows Arch. 2012; 461: 313-322
- Expression of terminal differentiation proteins defines stages of mouse mammary gland development.Vet Pathol. 2006; 43: 36-49
- Novel function of keratins 5 and 14 in proliferation and differentiation of stratified epithelial cells.Mol Biol Cell. 2011; 22: 4068-4078
- Overview of steroidogenic enzymes in the pathway from cholesterol to active steroid hormones.Endocr Rev. 2004; 25: 947-970
- Iodoacetic acid affects estrous cyclicity, ovarian gene expression, and hormone levels in mice.Biol Reprod. 2021; 105: 1030-1042
- Prenatal exposure to di(2-ethylhexyl) phthalate disrupts ovarian function in a transgenerational manner in female mice.Biol Reprod. 2018; 98: 130-145
- The influence of LepR tyrosine site mutations on mouse ovary development and related gene expression changes.PLoS One. 2015; 10: e0141800
- How many etiological subtypes of breast cancer: two, three, four, or more?.J Natl Cancer Inst. 2014; 106: dju165
- Managing early-stage breast cancer in your older patients.Oncology (Williston Park). 2006; 20: 1003-1012
- Breast cancer risk factors.Prz Menopauzalny. 2015; 14: 196-202
- Triple-negative breast cancer in the older population.Ann Oncol. 2012; 23: vi52-vi55
- Breast cancer and aging: results of the U13 conference breast cancer panel.Breast Cancer Res Treat. 2014; 146: 1-6
- Prognostic factors in elderly patients with breast cancer.BMC Surg. 2013; 13: S2
- Breast cancer beyond the age of mutation.Gerontology. 2016; 62: 434-442
- BRCA1 deficient mouse models to study pathogenesis and therapy of triple negative breast cancer.Breast Dis. 2010; 32: 85-97
- Exploiting mouse models to recapitulate clinical tumor dormancy and recurrence in breast cancer.Endocrinology. 2022; 163: bqac055
- Atlas of lobular breast cancer models: challenges and strategic directions.Cancers (Basel). 2021; 13: 5396
- Disruption of cyclin D1 nuclear export and proteolysis accelerates mammary carcinogenesis.Oncogene. 2008; 27: 1231-1242
- Altered AIB1 or AIB1Δ3 expression impacts ER[alpha] effects on mammary gland stromal and epithelial content.Mol Endocrinol. 2011; 25: 549-563
- Prolactin induces ER[alpha]-positive and ER[alpha]-negative mammary cancer in transgenic mice.Oncogene. 2003; 22: 4664-4674
- STAT1-deficient mice spontaneously develop estrogen receptor [alpha]-positive luminal mammary carcinomas.Breast Cancer Res. 2012; 14: R16
- Conditional over-expression of estrogen receptor alpha in a transgenic mouse model.Transgenic Res. 2002; 11: 361-372
- Apoptosis and remodeling of mammary gland tissue during involution proceeds through p53-independent pathways.Cell Growth Differ. 1996; 7: 13-20
- Responsiveness of Brca1 and Trp53 deficiency induced mammary preneoplasia to selective estrogen modulators versus an aromatase inhibitor in Mus musculus.Cancer Prev Res (Phila). 2017; 10: 244-254
- The PPAR[gamma] agonist efatutazone increases the spectrum of well-differentiated mammary cancer subtypes initiated by loss of full-length BRCA1 in association with TP53 haploinsufficiency.Am J Pathol. 2013; 182: 1976-1985
- Premalignant and malignant mammary lesions induced by MMTV and chemical carcinogens.J Mammary Gland Biol Neoplasia. 2008; 13: 271-277
- Mouse mammary gland whole mount density assessment across different morphologies using a bifurcated program for image processing.Am J Pathol. 2022; 192: 1407-1417
- STAR: ultrafast universal RNA-seq aligner.Bioinformatics. 2013; 29: 15-21
- Normalization of RNA-seq data using factor analysis of control genes or samples.Nat Biotechnol. 2014; 32: 896-902
- RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome.BMC Bioinformatics. 2011; 12: 323
- Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2.Genome Biol. 2014; 15: 550
- Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles.Proc Natl Acad Sci U S A. 2005; 102: 15545-15550
- The Molecular Signatures Database (MSigDB) hallmark gene set collection.Cell Syst. 2015; 1: 417-425
- Loss of EZH2 results in precocious mammary gland development and activation of STAT5-dependent genes.Nucleic Acids Res. 2015; 43: 8774-8789
- Gene Expression Omnibus: NCBI gene expression and hybridization array data repository.Nucleic Acids Res. 2002; 30: 207-210
- Mouse models in aging research.in: Fox J.G. Davisson M.T. Quimby F.W. Barthold S.W. Newcomer C.E. Smith A.L. The Mouse in Biomedical Research (Second Edition) History, Wild Mice, and Genetics. ed 2. American College of Laboratory Animal Medicine (Elsevier), Burlington, MA2007: 637-672
- Biology of primary breast cancer in older women beyond routine biomarkers.Breast Cancer. 2021; 28: 991-1001
- The greater impact of menopause on ER- than ER+ breast cancer incidence: a possible explanation (United States).Cancer Causes Control. 2002; 13: 7-14
- Positive regulation of estrogen receptor alpha in breast tumorigenesis.Cells. 2021; 10: 2966
- Estrogen receptor alpha in human breast cancer: occurrence and significance.J Mammary Gland Biol Neoplasia. 2000; 5: 271-281
- Obesity and breast cancer – role of estrogens and the molecular underpinnings of aromatase regulation in breast adipose tissue.Mol Cell Endocrinol. 2018; 466: 15-30
- Oestrogen-synthesising enzymes and breast cancer.Anticancer Res. 2009; 29: 1095-1109
- Deregulated estrogen receptor alpha expression in mammary epithelial cells of transgenic mice results in the development of ductal carcinoma in situ.Cancer Res. 2005; 65: 681-685
- Androgens and ovarian function: translation from basic discovery research to clinical impact.J Endocrinol. 2019; 242: R23-R50
- Key stages in mammary gland development - the alveolar switch: coordinating the proliferative cues and cell fate decisions that drive the formation of lobuloalveoli from ductal epithelium.Breast Cancer Res. 2006; 8: 207
- The “why and how” of cervical cancers and genital HPV infection.Cytojournal. 2022; 19: 22
- Epidemiology and pathophysiology of pregnancy-associated breast cancer: a review.Breast. 2017; 35: 136-141
- Postpartum breast cancer: mechanisms underlying its worse prognosis, treatment implications, and fertility preservation.Int J Gynecol Cancer. 2021; 31: 412-422
- Mechanism and preclinical prevention of increased breast cancer risk caused by pregnancy.Elife. 2013; 2: e00996
- The NFkappaB pathway and endocrine-resistant breast cancer.Endocr Relat Cancer. 2005; 12: S37-S46
Article info
Publication history
Published online: November 30, 2022
Accepted:
September 16,
2022
Footnotes
Tumorigenesis and Neoplastic Progression
Supported by NIH UH3CA213388 (P.A.F.) and NIH P30CA051008 (P.A.F.).
Disclosures: None declared.
Current address of W.W., Department of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington, DC.
Identification
Copyright
© 2023 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
