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Publications  >  Special Reports  >  2014  >  Breast Cancer (Issue 1)  >  

Anti-Androgen Not for Male Cancers Alone

By Jennifer Shepphird, PhD
Published Online: Dec 17,2014
breast cancer cell A potential pathogenic role for the androgen receptor (AR) exists for some breast cancer (BC) subtypes according to 2 new studies presented at the San Antonio Breast Cancer Symposium (SABCS) 2014.

Research from the University of Colorado Cancer Center in Denver showed that preventing AR nuclear localization slows tumor growth in estrogen receptor positive (ER+) BC and also demonstrated that certain triple-negative breast cancer (TNBC) subtypes depend on AR activity. In addition, the researchers showed that simultaneous inhibition of AR and the HER2/PI3K/mTOR pathway may be more effective than inhibition of the HER2/PI3K/mTOR pathway alone.

The AR is involved in prostate cancer, similar to the involvement of the estrogen receptor (ER) in breast cancer. However, about 75% of breast cancers express AR, and the expression varies by subtype, appearing in approximately 88% of ER+ BC, 50% of HER2+ BC, and 20% of TNBC.1 In postmenopausal women, the level of circulating androgens is greater than estrogen, and the AR is more widely expressed in BC than estrogen or progesterone receptors.

Jennifer Richer, PhD, head of the research team that produced the studies commented that a major revolution may be about to occur for the treatment of breast cancer. “We've known for years that prostate cancer is driven by androgens, and now it's increasingly clear that androgens and androgen receptors can influence many breast cancers as well,”2 Richer noted in a written release from the University of Colorado. “Targeting androgen receptors in breast cancer gives us a new way to attack the disease," she added.

With no targeted therapies currently available, TNBC has a poor prognosis despite initial responses to conventional chemotherapy. Reports have shown that up to one-third of TNBCs express AR, and research presented at SABCS showed that in AR+ TNBC, inhibiting AR activity with the antagonist enzalutamide (ENZ) prevented AR nuclear localization in response to ligand binding (dihydrotestosterone), reduced proliferation in 2D culture, and decreased anchorage-independent growth.

In addition to reduced proliferation, treatment with ENZ altered cellular morphology and significantly decreased cancer cell migration and invasion. Microarray profiling suggested that AR influences cell proliferation, migration, and invasion through regulation of the EGFR ligand amphiregulin, a protein previously implicated in cancer progression.3

According to Valerie Barton, a graduate student in the Richer lab and lead author on the study, drugs such as ENZ block the action of androgen receptors and decrease the production of amphiregulin, thereby killing TNBC cells.

AR activation affects several cellular functions and signalling networks, including the HER2/PI3K/mTOR pathway. Inhibitors of the pathway (anti-HER2 trastuzumab [TRAS] and anti-mTOR everolimus [EVE]) have shown clinical benefit, and another line of inquiry from the Richer lab sought to determine whether AR inhibition (using ENZ) would enhance the efficacy of these agents.

HER2+ and TNBC cell lines were treated with ENZ, TRAS, and EVE alone or in combination. The combination of ENZ with TRAS or EVE inhibited cell proliferation more effectively than either drug alone. The researchers, led by Michael Gordon, PhD, concluded that through a distinct mechanism, AR inhibition acts synergistically with inhibitors of the HER2/PI3K/mTOR pathway to decrease proliferation and that “combination therapies containing ENZ may provide benefit for multiple BC subtypes, including HER2+ and triple negative BC.”4

For tumors expressing ER+, controversy exists over the role of AR. In the absence of estradiol (E2), activated AR increases growth of ER+ breast cancer cells, and AR inhibition by bicalutamide (Bic) or ENZ blocks this proliferation. However, ENZ, but not Bic, also inhibits E2-mediated proliferation of ER+ BC cells. Because ENZ blocks nuclear localization of ligand-bound AR, the current study evaluated whether AR nuclear localization is necessary for E2-mediated proliferation in ER+/AR+ BC. Results showed that ENZ inhibited E2-induced proliferation. The agent worked synergistically with ER antagonists, tamoxifen and fulvestrant. E2-induced expression of ER target genes was inhibited by ENZ but not by Bic.5

Treatment with dihydrotestosterone (DHT) or E2 induced translocation of AR to the nucleus. The E2-induced translocation only occurred in ER+ cells, further suggesting a role for AR in E2-induced ER activity. ENZ inhibited AR nuclear translocation, and in vivo, ENZ inhibited E2-induced tumor growth as effectively as tamoxifen. The combination of tamoxifen and ENZ was more effective than either agent alone.

Nicholas D’Amato, lead author on the study and a postdoctoral researcher in the Richer lab, explained that tamoxifen and other drugs that target ER+ breast cancer are effective, but resistance and recurrence are still big problems.

Up to half of ER+ tumors are resistant to endocrine therapies, and all metastatic ER+ BCs acquire resistance. AR overexpression induces tamoxifen resistance, and previous research from the group showed that the ratio of AR to ER influences the response to therapy. The research presented at the conference showed that the nuclear localization of AR decreases ER activity and tumor growth in ER+/AR+ cancers, and inhibition by ENZ may be effective, particularly in combination with antiestrogen therapies, because it effects ER through an indirect mechanism.

Clinical Pearls

  • According to 2 new studies presented at SABCS 2014, a potential pathogenic role for the androgen receptor (AR) exists for some breast cancer (BC) subtypes.
  • In AR+ TNBC, inhibiting AR activity with the antagonist enzalutamide prevented AR nuclear localization in response to ligand binding (dihydrotestosterone), reduced proliferation in 2D culture, and decreased anchorage-independent growth. It also altered cellular morphology and significantly decreased cancer cell migration and invasion.
  • Researchers treated HER2+ and TNBC cell lines with enzalutamide, trastuzumab, and everolimus alone or in combination and demonstrated that the combination of enzalutamide with trastuzumab or everolimus inhibited cell proliferation more effectively than either drug alone
  • Results of one study showed that enzalutamide inhibited estradiol-induced proliferation and that it worked synergistically with ER antagonists, tamoxifen and fulvestrant.
The 3 studies from the Richer lab point to a pathogenic role for AR in some breast cancers, and AR inhibition by ENZ demonstrates its potential as a therapeutic target in certain BC subtypes. “Women with breast cancer do not routinely receive testing for the androgen receptor,” Richer noted.

“If the androgen receptor is outside the nucleus, both estrogen and androgen-driven tumor growth is inhibited,” noted Richer in a written release. “Our research suggests that the androgen receptor may serve as a therapeutic target in both estrogen receptor-positive and negative breast cancers.”

References

  1. Collins LC, Cole KS, Marotti JD, et al. Androgen receptor expression in breast cancer in relation to molecular phenotype: results from the Nurses' Health Study. Mod Pathol. 2011;24:924-931.
  2. Three San Antonio studies target androgen in breast cancer [news release]. Denver, CO: December 11, 2014. http://www.eurekalert.org/pub_releases/2014-12/uocd-3sa121014.php. Accessed December 16, 2014.
  3. Barton VN, D’Amato NC, Gordon MA, et al. Multiple subtypes of triple negative breast cancer are dependent on androgen receptor. Presented at: San Antonio Breast Cancer Symposium; December 9-13, 2014; San Antonio, Texas. Abstract P3-04-02.
  4. Gordon MA, D’Amato N, Gu H, et al. Targeting multiple pathways in breast cancer: androgen receptor, HER2, and mTOR. Presented at: San Antonio Breast Cancer Symposium; December 9-13, 2014; San Antonio, Texas. Abstract P6-03-07.
  5. D’Amato NC, Jacobsen BM, Cochrane DR, et al. Inhibiting androgen receptor nuclear localization decreases estrogen receptor (ER) activity and tumor growth in ER+ breast cancer. Presented at: San Antonio Breast Cancer Symposium; December 9-13, 2014; San Antonio, Texas. Abstract P3-04-06.

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Anti-Androgen Not for Male Cancers Alone
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