Aromatase Expression Increases the Survival and Malignancy of Estrogen Receptor Positive Breast Cancer Cells

Mukhopadhyay, Keya De; Zhao, Liang; Bandyopadhyay, Abhik; Kirma, Nameer B.; Tekmal, Rajeshwar Rao; Wang, Shui; Sun, Lu

doi:10.1371/journal.pone.0121136

Cited by 22 publications

(17 citation statements)

References 23 publications

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“…The spontaneously immortalized human mammary epithelial MCF-10A cells were obtained from the Michigan Cancer Foundation and cultured in the DMEM/F-12 medium originally used to develop the cell line [26]. Human breast cancer ZR75-1 and MCF-7 cell lines were obtained from ATCC and the Michigan Cancer Foundation, respectively, and cultured in a supplemental McCoy's 5A medium containing 10% fetal bovine serum [27]. Retroviral packaging PA317 cells were obtained from ATCC and cultured in DMEM containing 10% fetal bovine serum.…”

Section: Methodsmentioning

confidence: 99%

Estrogen receptor alpha inhibits senescence-like phenotype and facilitates transformation induced by oncogenic ras in human mammary epithelial cells

et al. 2016

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Exposure to estrogen has long been associated with an increased risk of developing breast cancer. However, how estrogen signaling promotes breast carcinogenesis remains elusive. Senescence is known as an important protective response to oncogenic events. We aimed to elucidate the role of estrogen receptor alpha (ERα) on senescence in transformed human mammary epithelial cells and breast cancer cells. Our results show that ectopic expression of oncoprotein H-ras-V12 in immortalized human mammary epithelial cells (HMEC) significantly inhibited the phosphorylation of the retinoblastoma protein (Rb) and increased the activity of the senescence-associated beta-galactosidase (SA-β-Gal). These senescence-like phenotypes were reversed by ectopic expression of ERα. Similar inhibition of the H-ras-V12-induced SA-β-Gal activity by ERα was also observed in the human mammary epithelial MCF-10A cells. Co-expression of ERα and H-ras-V12 resulted in HMEC anchorage-independent growth in vitro and tumor formation in vivo. Furthermore, inhibition of ERα expression induced senescence-like phenotypes in ERα positive human breast cancer cells such as increased activity of SA-β-Gal, decreased phosphorylation of RB, and loss of mitogenic activity. Thus, the suppression of cellular senescence induced by oncogenic signals may be a major mechanism by which ERα promotes breast carcinogenesis.

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Section: Methodsmentioning

confidence: 99%

Estrogen receptor alpha inhibits senescence-like phenotype and facilitates transformation induced by oncogenic ras in human mammary epithelial cells

et al. 2016

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“…Aromatase is elevated in most breast cancers [ 32 ] and interestingly in other cancers not typically associated with dysregulated steroidogenesis such as NSCLC [ 33 ] and colon cancer [ 34 ]. Aromatase has even been linked with metastasis [ 35 , 36 ] and transgenic models demonstrate its oncogenicity [ 37 , 38 ], yet many unknowns remain about the diverse pathway(s) that drive CYP19A1 overexpression. This question is important because tumor-associated estrogen production was shown to be significantly higher than levels in the plasma of post-menopausal patients or in normal tissue [ 39 ].…”

Section: Introductionmentioning

confidence: 99%

DVL1 and DVL3 differentially localize to CYP19A1 promoters and regulate aromatase mRNA in breast cancer cells

et al. 2018

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The CYP19A1 gene encodes aromatase, an enzyme that converts androgens into estrogens and consequently directly contributes to both the depletion of androgens and the synthesis of estrogens in several organs. Aromatase is critical for diverse biological processes such as proliferation, regulation of fat metabolism and hormone signaling. Additionally, it is also overexpressed in diverse cancers and drives hormone-dependent tumor progression and increases 17-β-estradiol (E2) within tumors and the tumor microenvironment. Although the inhibition of E2 production via aromatase inhibitors represents a major therapeutic paradigm in clinical oncology, fundamental questions regarding how cancer cells gain the capacity to overexpress aromatase remain unanswered. Multiple tissue-specific CYP19A1 promoters are known to be aberrantly active in tumors, yet how this occurs is unclear. Here, for the first time, we report that Dishevelled (DVL) proteins, which are key mediators of Wnt signaling, regulate aromatase expression in multiple breast cancer cell lines. We also report that DVL enters the nucleus and localizes to at least two different CYP19A1 promoters (pII and I.4) previously reported to drive overexpression in breast tumors and to a very distal CYP19A1 placental promoter (I.1) that remains poorly characterized. We go on to demonstrate that DVL-1 and DVL-3 loss of function leads to differential changes in various aromatase transcripts and in E2 production. The report, herein, uncovers a new regulator of CYP19A1 transcription and for the first time demonstrates that DVL, a critical mediator of WNT signaling, contributes to aberrant breast cancer-associated estrogen production.

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“…In postmenopausal women, extragonadal sites such as mesenchymal cells of the adipose tissue and skin, bone, and brain express aromatase and become the main source of estrogen. The estrogen produced by breast adipose tissue is strongly implicated in promoting the development and growth of ER-positive breast cancer [12]. Shibahara et al [13] reported that the aromatase status of a primary tumor generally represents the status of metastatic lymph nodes, and aromatase immunoreactivity was detected in the adipose tissue surrounding the lymph node.…”

Section: Discussion/conclusionmentioning

confidence: 99%

Localized Cutaneous Adverse Event Induced by Anastrozole as Adjuvant Treatment for Breast Cancer: A Case Report

et al. 2019

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Cutaneous adverse events caused by aromatase inhibitors have been reported to be rare. We describe a rare case of a cutaneous adverse event that developed in a cancer-affected breast after aromatase inhibitor treatment. A 72-year-old postmenopausal female patient who was diagnosed with stage IA breast cancer received anastrozole as adjuvant treatment. Six months after the initiation of anastrozole, she developed an irregularly shaped purpuric plaque with several purpuric papules surrounding the postoperative scar on her left breast. Histological findings revealed capillary vessel proliferation and expansion, with hemorrhage in the superficial dermis. Immunohistochemistry of the skin biopsy specimen revealed hormone receptor expression limited to the vascular endothelial cells of the proliferating and expanding vessels. We believe that anastrozole induced a change in the local estrogen level, which affected the hormone receptor-positive endothelial cells in the dermis near the primary lesion of the breast cancer and caused a cutaneous adverse event only in the aforementioned area.

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Aromatase Expression Increases the Survival and Malignancy of Estrogen Receptor Positive Breast Cancer Cells

Cited by 22 publications

References 23 publications

Estrogen receptor alpha inhibits senescence-like phenotype and facilitates transformation induced by oncogenic ras in human mammary epithelial cells

Estrogen receptor alpha inhibits senescence-like phenotype and facilitates transformation induced by oncogenic ras in human mammary epithelial cells

DVL1 and DVL3 differentially localize to CYP19A1 promoters and regulate aromatase mRNA in breast cancer cells

Localized Cutaneous Adverse Event Induced by Anastrozole as Adjuvant Treatment for Breast Cancer: A Case Report

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