ARe we there yet? Understanding androgen receptor signaling in breast cancer

Michmerhuizen, Anna R.; Spratt, Daniel E.; Pierce, Lori J.; Speers, Corey

doi:10.1038/s41523-020-00190-9

Cited by 75 publications

(56 citation statements)

References 220 publications

(307 reference statements)

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“…Interestingly, MOE:PTEN shRNA induced testosterone when grown in proximity of the ovary, but were not susceptible to androgen-induced proliferation, nor were they effected by bicalutamide. This data is consistent with existing studies that have examined the interactions between PTEN and AR in breast and prostate cancer showing that PTEN and AR directly interact and that loss of PTEN, and commensurate increased PI3K activity, reduces AR signaling [50][51][52]. While our data suggests that PTEN deficient tubal cells may themselves be insulated from the pro-proliferative effects of ovarian androgenic secretions, the surrounding epithelium and earlier precursor lesions such as SCOUTs remain susceptible.…”

Section: Discussionsupporting

confidence: 92%

Fallopian Tube-Derived Tumor Cells Induce Testosterone Secretion from the Ovary, Increasing Epithelial Proliferation and Invasion

Colina

Zink

Eliadis

et al. 2021

Cancers

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The fallopian tube epithelium is the site of origin for a majority of high grade serous ovarian carcinomas (HGSOC). The chemical communication between the fallopian tube and the ovary in the development of HGSOC from the fallopian tube is of interest since the fimbriated ends in proximity of the ovary harbor serous tubal intraepithelial carcinoma (STICs). Epidemiological data indicates that androgens play a role in ovarian carcinogenesis; however, the oncogenic impact of androgen exposure on the fallopian tube, or tubal neoplastic precursor lesions, has yet to be explored. In this report, imaging mass spectrometry identified that testosterone is produced by the ovary when exposed to tumorigenic fallopian tube derived PTEN deficient cells. Androgen exposure increased cellular viability, proliferation, and invasion of murine cell models of healthy fallopian tube epithelium and PAX2 deficient models of the preneoplastic secretory cell outgrowths (SCOUTs). Proliferation and invasion induced by androgen was reversed by co-treatment with androgen receptor (AR) antagonist, bicalutamide. Furthermore, ablation of phosphorylated ERK reversed proliferation, but not invasion. Investigation of two hyperandrogenic rodent models of polycystic ovarian syndrome revealed that peripheral administration of androgens does not induce fallopian proliferation in vivo. These data suggest that tumorigenic lesions in the fallopian tube may induce an androgenic microenvironment proximal to the ovary, which may in turn promote proliferation of the fallopian tube epithelium and preneoplastic lesions.

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Section: Discussionsupporting

confidence: 92%

Fallopian Tube-Derived Tumor Cells Induce Testosterone Secretion from the Ovary, Increasing Epithelial Proliferation and Invasion

Colina

Zink

Eliadis

et al. 2021

Cancers

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“…The prognostic value of AR expression in breast cancer has been evaluated in multiple breast cancer cohorts (14,(23)(24)(25)(26). Steroid hormone nuclear receptors like estrogen and androgen receptors often crosstalk and influence the action of each other (13,27).…”

Section: Discussionmentioning

confidence: 99%

Pre-Menopausal Women With Breast Cancers Having High AR/ER Ratios in the Context of Higher Circulating Testosterone Tend to Have Poorer Outcomes

et al. 2021

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PurposeWomen with breast tumors with higher expression of AR are in general known to have better survival outcomes while a high AR/ER ratio is associated with poor outcomes in hormone receptor positive breast cancers mostly in post menopausal women. We have evaluated the AR/ER ratio in the context of circulating androgens specifically in patients younger than 50 years most of whom are pre-menopausal and hence have a high estrogenic hormonal milieu.MethodsTumor samples from patients 50 years or younger at first diagnosis were chosen from a larger cohort of 270 patients with median follow-up of 72 months. Expression levels of ER and AR proteins were detected by immunohistochemistry (IHC) and the transcript levels by quantitative PCR. Ciculating levels of total testosterone were estimated from serum samples. A ratio of AR/ER was derived using the transcript levels, and tumors were dichotomized into high and low ratio groups based on the third quartile value. Survival and the prognostic significance of the ratio was compared between the low and high ratio groups in all tumors and also within ER positive tumors. Results were further validated in external datasets (TCGA and METABRIC).ResultsEighty-eight (32%) patients were ≤50 years, with 22 having high AR/ER ratio calculated using the transcript levels. Circulating levels of total testosterone were higher in women whose tumors had a high AR/ER ratio (p = 0.02). Tumors with high AR/ER ratio had significantly poorer disease-free survival than those with low AR/ER ratio [HR-2.6 (95% CI-1.02–6.59) p = 0.04]. Evaluation of tumors with high AR/ER ratio within ER positive tumors alone reconfirmed the prognostic relevance of the high AR/ER ratio with a significant hazard ratio of 4.6 (95% CI-1.35–15.37, p = 0.01). Similar trends were observed in the TCGA and METABRIC dataset.ConclusionOur data in pre-menopausal women with breast cancer suggest that it is not merely the presence or absence of AR expression but the relative activity of ER, as well as the hormonal milieu of the patient that determine clinical outcomes, indicating that both context and interactions ultimately influence tumor behavior.

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“…T probably exerts its action through its union to the androgen receptor (AR). AR is expressed in 15–30% of TNBC, and some studies have suggested that AR might function in place of ER in its absence [ 32 ]. Contrarily, when cells were treated with STX-64, DHT secretions were significantly diminished.…”

Section: Discussionmentioning

confidence: 99%

Blocking Estrogen Synthesis Leads to Different Hormonal Responses in Canine and Human Triple Negative Inflammatory Breast Cancer

Cáceres

Monsalve

Alonso-Diez

et al. 2021

Cancers

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Blocking estrogen synthesis by inhibitors of estrogen synthesis is a widely used therapy against estrogen receptor-positive tumors. However, these therapies are less effective in negative expression tumors. Therefore, this study determined the effectiveness of anti-aromatase and anti-sulfatase therapies in canine and human inflammatory breast cancer. Cell cultures and xenografts from IPC-366 and SUM149 were treated with different doses of letrozole (anti-aromatase) and STX-64 (anti-sulfatase), in order to observe their effectiveness in terms of cell proliferation, tumor progression, and the appearance of metastases and hormonal profiles. The results revealed that both treatments are effective in vitro since they reduce cell proliferation and decrease the secreted estrogen levels. In xenograft mice, while treatment with letrozole reduces tumor progression by 30–40%, STX-64 increases tumor progression by 20%. The hormonal results obtained determined that STX-64 produced an increase in circulating and intratumoral levels of estradiol, which led to an increase in tumor progression. However, letrozole was able to block estrogen synthesis by decreasing the levels of circulating and intratumoral estrogen and thus slowing down tumor progression. In conclusion, letrozole can be an effective treatment for canine and human inflammatory breast cancer. The knowledge of the hormonal profile of breast tumors reflects useful information on the effectiveness of different endocrine treatments.

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ARe we there yet? Understanding androgen receptor signaling in breast cancer

Cited by 75 publications

References 220 publications

Fallopian Tube-Derived Tumor Cells Induce Testosterone Secretion from the Ovary, Increasing Epithelial Proliferation and Invasion

Fallopian Tube-Derived Tumor Cells Induce Testosterone Secretion from the Ovary, Increasing Epithelial Proliferation and Invasion

Pre-Menopausal Women With Breast Cancers Having High AR/ER Ratios in the Context of Higher Circulating Testosterone Tend to Have Poorer Outcomes

Blocking Estrogen Synthesis Leads to Different Hormonal Responses in Canine and Human Triple Negative Inflammatory Breast Cancer

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