Selective Androgen Receptor Modulators (SARMs) negatively regulate triple-negative breast cancer growth and epithelial:mesenchymal stem cell signaling

Ramesh Narayanan, Sunjoo Ahn, Misty D. Cheney, Muralimohan Yepuru, Duane Miller, Mitchell S. Steiner, James T. Dalton

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Introduction: The androgen receptor (AR) is the most highly expressed steroid receptor in breast cancer with 75-95% of estrogen receptor (ER)-positive and 40-70% of ER-negative breast cancers expressing AR. Though historically breast cancers were treated with steroidal androgens, their use fell from favor because of their virilizing side effects and the emergence of tamoxifen. Nonsteroidal, tissue selective androgen receptor modulators (SARMs) may provide a novel targeted approach to exploit the therapeutic benefits of androgen therapy in breast cancer. Materials and Methods: Since MDA-MB-453 triple-negative breast cancer cells express mutated AR, PTEN, and p53, MDA-MB-231 triple-negative breast cancer cells stably expressing wildtype AR (MDA-MB-231-AR) were used to evaluate the in vitro and in vivo anti-proliferative effects of SARMs. Microarray analysis and epithelial:mesenchymal stem cell (MSC) coculture signaling studies were performed to understand the mechanisms of action. Results: Dihydrotestosterone and SARMs, but not bicalutamide, inhibited the proliferation of MDA-MB-231-AR. The SARMs reduced the MDA-MB-231-AR tumor growth and tumor weight by greater than 90%, compared to vehicle-treated tumors. SARM treatment inhibited the intratumoral expression of genes and pathways that promote breast cancer development through its actions on the AR. SARM treatment also inhibited the metastasis-promoting paracrine factors, IL6 and MMP13, and subsequent migration and invasion of epithelial:MSC co-cultures. Conclusion: 1. AR stimulation inhibits paracrine factors that are important for MSC interactions and breast cancer invasion and metastasis. 2. SARMs may provide promise as novel targeted therapies to treat AR-positive triple-negative breast cancer.

Original languageEnglish (US)
Article numbere103202
JournalPloS one
Volume9
Issue number7
DOIs
StatePublished - Jul 29 2014

Fingerprint

Triple Negative Breast Neoplasms
Cell signaling
Androgen Receptors
Stem cells
Mesenchymal Stromal Cells
breast neoplasms
Modulators
stem cells
epithelial cells
Growth
Breast Neoplasms
Tumors
androgen receptors
coculture
Coculture Techniques
androgens
metastasis
Estrogen Receptors
therapeutics
Androgens

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Selective Androgen Receptor Modulators (SARMs) negatively regulate triple-negative breast cancer growth and epithelial:mesenchymal stem cell signaling. / Narayanan, Ramesh; Ahn, Sunjoo; Cheney, Misty D.; Yepuru, Muralimohan; Miller, Duane; Steiner, Mitchell S.; Dalton, James T.

In: PloS one, Vol. 9, No. 7, e103202, 29.07.2014.

Research output: Contribution to journalArticle

Narayanan, Ramesh ; Ahn, Sunjoo ; Cheney, Misty D. ; Yepuru, Muralimohan ; Miller, Duane ; Steiner, Mitchell S. ; Dalton, James T. / Selective Androgen Receptor Modulators (SARMs) negatively regulate triple-negative breast cancer growth and epithelial:mesenchymal stem cell signaling. In: PloS one. 2014 ; Vol. 9, No. 7.
@article{70d1a4f7e26b40cfa1589619fd0b7bc2,
title = "Selective Androgen Receptor Modulators (SARMs) negatively regulate triple-negative breast cancer growth and epithelial:mesenchymal stem cell signaling",
abstract = "Introduction: The androgen receptor (AR) is the most highly expressed steroid receptor in breast cancer with 75-95{\%} of estrogen receptor (ER)-positive and 40-70{\%} of ER-negative breast cancers expressing AR. Though historically breast cancers were treated with steroidal androgens, their use fell from favor because of their virilizing side effects and the emergence of tamoxifen. Nonsteroidal, tissue selective androgen receptor modulators (SARMs) may provide a novel targeted approach to exploit the therapeutic benefits of androgen therapy in breast cancer. Materials and Methods: Since MDA-MB-453 triple-negative breast cancer cells express mutated AR, PTEN, and p53, MDA-MB-231 triple-negative breast cancer cells stably expressing wildtype AR (MDA-MB-231-AR) were used to evaluate the in vitro and in vivo anti-proliferative effects of SARMs. Microarray analysis and epithelial:mesenchymal stem cell (MSC) coculture signaling studies were performed to understand the mechanisms of action. Results: Dihydrotestosterone and SARMs, but not bicalutamide, inhibited the proliferation of MDA-MB-231-AR. The SARMs reduced the MDA-MB-231-AR tumor growth and tumor weight by greater than 90{\%}, compared to vehicle-treated tumors. SARM treatment inhibited the intratumoral expression of genes and pathways that promote breast cancer development through its actions on the AR. SARM treatment also inhibited the metastasis-promoting paracrine factors, IL6 and MMP13, and subsequent migration and invasion of epithelial:MSC co-cultures. Conclusion: 1. AR stimulation inhibits paracrine factors that are important for MSC interactions and breast cancer invasion and metastasis. 2. SARMs may provide promise as novel targeted therapies to treat AR-positive triple-negative breast cancer.",
author = "Ramesh Narayanan and Sunjoo Ahn and Cheney, {Misty D.} and Muralimohan Yepuru and Duane Miller and Steiner, {Mitchell S.} and Dalton, {James T.}",
year = "2014",
month = "7",
day = "29",
doi = "10.1371/journal.pone.0103202",
language = "English (US)",
volume = "9",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "7",

}

TY - JOUR

T1 - Selective Androgen Receptor Modulators (SARMs) negatively regulate triple-negative breast cancer growth and epithelial:mesenchymal stem cell signaling

AU - Narayanan, Ramesh

AU - Ahn, Sunjoo

AU - Cheney, Misty D.

AU - Yepuru, Muralimohan

AU - Miller, Duane

AU - Steiner, Mitchell S.

AU - Dalton, James T.

PY - 2014/7/29

Y1 - 2014/7/29

N2 - Introduction: The androgen receptor (AR) is the most highly expressed steroid receptor in breast cancer with 75-95% of estrogen receptor (ER)-positive and 40-70% of ER-negative breast cancers expressing AR. Though historically breast cancers were treated with steroidal androgens, their use fell from favor because of their virilizing side effects and the emergence of tamoxifen. Nonsteroidal, tissue selective androgen receptor modulators (SARMs) may provide a novel targeted approach to exploit the therapeutic benefits of androgen therapy in breast cancer. Materials and Methods: Since MDA-MB-453 triple-negative breast cancer cells express mutated AR, PTEN, and p53, MDA-MB-231 triple-negative breast cancer cells stably expressing wildtype AR (MDA-MB-231-AR) were used to evaluate the in vitro and in vivo anti-proliferative effects of SARMs. Microarray analysis and epithelial:mesenchymal stem cell (MSC) coculture signaling studies were performed to understand the mechanisms of action. Results: Dihydrotestosterone and SARMs, but not bicalutamide, inhibited the proliferation of MDA-MB-231-AR. The SARMs reduced the MDA-MB-231-AR tumor growth and tumor weight by greater than 90%, compared to vehicle-treated tumors. SARM treatment inhibited the intratumoral expression of genes and pathways that promote breast cancer development through its actions on the AR. SARM treatment also inhibited the metastasis-promoting paracrine factors, IL6 and MMP13, and subsequent migration and invasion of epithelial:MSC co-cultures. Conclusion: 1. AR stimulation inhibits paracrine factors that are important for MSC interactions and breast cancer invasion and metastasis. 2. SARMs may provide promise as novel targeted therapies to treat AR-positive triple-negative breast cancer.

AB - Introduction: The androgen receptor (AR) is the most highly expressed steroid receptor in breast cancer with 75-95% of estrogen receptor (ER)-positive and 40-70% of ER-negative breast cancers expressing AR. Though historically breast cancers were treated with steroidal androgens, their use fell from favor because of their virilizing side effects and the emergence of tamoxifen. Nonsteroidal, tissue selective androgen receptor modulators (SARMs) may provide a novel targeted approach to exploit the therapeutic benefits of androgen therapy in breast cancer. Materials and Methods: Since MDA-MB-453 triple-negative breast cancer cells express mutated AR, PTEN, and p53, MDA-MB-231 triple-negative breast cancer cells stably expressing wildtype AR (MDA-MB-231-AR) were used to evaluate the in vitro and in vivo anti-proliferative effects of SARMs. Microarray analysis and epithelial:mesenchymal stem cell (MSC) coculture signaling studies were performed to understand the mechanisms of action. Results: Dihydrotestosterone and SARMs, but not bicalutamide, inhibited the proliferation of MDA-MB-231-AR. The SARMs reduced the MDA-MB-231-AR tumor growth and tumor weight by greater than 90%, compared to vehicle-treated tumors. SARM treatment inhibited the intratumoral expression of genes and pathways that promote breast cancer development through its actions on the AR. SARM treatment also inhibited the metastasis-promoting paracrine factors, IL6 and MMP13, and subsequent migration and invasion of epithelial:MSC co-cultures. Conclusion: 1. AR stimulation inhibits paracrine factors that are important for MSC interactions and breast cancer invasion and metastasis. 2. SARMs may provide promise as novel targeted therapies to treat AR-positive triple-negative breast cancer.

UR - http://www.scopus.com/inward/record.url?scp=84904965441&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84904965441&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0103202

DO - 10.1371/journal.pone.0103202

M3 - Article

VL - 9

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 7

M1 - e103202

ER -