Limits...
Biologic roles of estrogen receptor-β and insulin-like growth factor-2 in triple-negative breast cancer.

Hamilton N, Márquez-Garbán D, Mah V, Fernando G, Elshimali Y, Garbán H, Elashoff D, Vadgama J, Goodglick L, Pietras R - Biomed Res Int (2015)

Bottom Line: To assess ERβ effects on proliferation, ERβ expression in TNBC cells was silenced using shRNA, resulting in a significant reduction in TNBC proliferation.Growth-stimulating effects of ERβ may be due in part to downstream actions that promote VEGF, amphiregulin, and Wnt-10b secretion, other factors associated with tumor promotion.In vivo, insulin-like growth factor-2 (IGF-2), along with ERβ1, is significantly expressed in TNBC and stimulates high ERβ mRNA in TNBC cells.

View Article: PubMed Central - PubMed

Affiliation: UCLA School of Nursing, Los Angeles, CA 90095, USA ; UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA 90095, USA.

ABSTRACT
Triple-negative breast cancer (TNBC) occurs in 10-15% of patients yet accounts for almost half of all breast cancer deaths. TNBCs lack expression of estrogen and progesterone receptors and HER-2 overexpression and cannot be treated with current targeted therapies. TNBCs often occur in African American and younger women. Although initially responsive to some chemotherapies, TNBCs tend to relapse and metastasize. Thus, it is critical to find new therapeutic targets. A second ER gene product, termed ERβ, in the absence of ERα may be such a target. Using human TNBC specimens with known clinical outcomes to assess ERβ expression, we find that ERβ1 associates with significantly worse 5-year overall survival. Further, a panel of TNBC cell lines exhibit significant levels of ERβ protein. To assess ERβ effects on proliferation, ERβ expression in TNBC cells was silenced using shRNA, resulting in a significant reduction in TNBC proliferation. ERβ-specific antagonists similarly suppressed TNBC growth. Growth-stimulating effects of ERβ may be due in part to downstream actions that promote VEGF, amphiregulin, and Wnt-10b secretion, other factors associated with tumor promotion. In vivo, insulin-like growth factor-2 (IGF-2), along with ERβ1, is significantly expressed in TNBC and stimulates high ERβ mRNA in TNBC cells. This work may help elucidate the interplay of metabolic and growth factors in TNBC.

Show MeSH

Related in: MedlinePlus

ERβ1 expression in archival TNBC specimens. Representative examples are shown of IHC staining of tumor and nonmalignant tissue specimens using anti-ERβ1 antibody (AbDSerotec PPG5/10). (a) TNBC specimen shows nuclear (and cytoplasmic) immunostaining of ERβ1 at low magnification. (b) The same TNBC specimen shows nuclear (and cytoplasmic) immunostaining of ERβ1 at higher magnification. (c) Expression of nuclear ERβ1 is also observed in neighboring nonmalignant mammary tissue from the clinical specimen used in panels (a) and (b). (d) Negative ERβ1 detected in a different clinical specimen as shown as comparison. Antibody binding was detected by using the “Envision+” amplification system followed by chromogen detection with diaminobenzidine (DAKO). Sections were counterstained with Harris hematoxylin followed by dehydration through graded alcohol solutions and mounting. See Table 2 for a summary of findings on all TNBC cases examined.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4385615&req=5

fig1: ERβ1 expression in archival TNBC specimens. Representative examples are shown of IHC staining of tumor and nonmalignant tissue specimens using anti-ERβ1 antibody (AbDSerotec PPG5/10). (a) TNBC specimen shows nuclear (and cytoplasmic) immunostaining of ERβ1 at low magnification. (b) The same TNBC specimen shows nuclear (and cytoplasmic) immunostaining of ERβ1 at higher magnification. (c) Expression of nuclear ERβ1 is also observed in neighboring nonmalignant mammary tissue from the clinical specimen used in panels (a) and (b). (d) Negative ERβ1 detected in a different clinical specimen as shown as comparison. Antibody binding was detected by using the “Envision+” amplification system followed by chromogen detection with diaminobenzidine (DAKO). Sections were counterstained with Harris hematoxylin followed by dehydration through graded alcohol solutions and mounting. See Table 2 for a summary of findings on all TNBC cases examined.

Mentions: Several reports indicate that ERβ expression in node-positive breast cancer is a biomarker for more aggressive disease [8, 21]. For these studies, we used 14 archival TNBC specimens with demographic characteristics including American Joint Committee on Cancer (AJCC) stages provided in Table 1. Using immunohistochemistry, specific ERβ1 staining was observed and scored in nuclear sites, with our observations noted in Table 2. Representative immune staining patterns are shown in Figure 1. Of note, we also observed evidence of diffuse extranuclear ERβ1 staining in most specimens but this staining was not scored or analyzed for this report. In further analyses, we assessed the clinical outcome of 14 patients with a 5-year follow-up whose tumors expressed or did not express ERβ1. In this group of patients with advanced TNBC, overall survival (OS) was significantly worse for TNBC patients with high nuclear ERβ1 (positive) as compared to those with low (negative) ERβ1 (P < 0.001; see Figure 2). Finally, we note that, of the African American patients included in our sample of 14 TNBC patients (11 Caucasian and 3 African American women), all three had tumors that were ERβ1-positive.


Biologic roles of estrogen receptor-β and insulin-like growth factor-2 in triple-negative breast cancer.

Hamilton N, Márquez-Garbán D, Mah V, Fernando G, Elshimali Y, Garbán H, Elashoff D, Vadgama J, Goodglick L, Pietras R - Biomed Res Int (2015)

ERβ1 expression in archival TNBC specimens. Representative examples are shown of IHC staining of tumor and nonmalignant tissue specimens using anti-ERβ1 antibody (AbDSerotec PPG5/10). (a) TNBC specimen shows nuclear (and cytoplasmic) immunostaining of ERβ1 at low magnification. (b) The same TNBC specimen shows nuclear (and cytoplasmic) immunostaining of ERβ1 at higher magnification. (c) Expression of nuclear ERβ1 is also observed in neighboring nonmalignant mammary tissue from the clinical specimen used in panels (a) and (b). (d) Negative ERβ1 detected in a different clinical specimen as shown as comparison. Antibody binding was detected by using the “Envision+” amplification system followed by chromogen detection with diaminobenzidine (DAKO). Sections were counterstained with Harris hematoxylin followed by dehydration through graded alcohol solutions and mounting. See Table 2 for a summary of findings on all TNBC cases examined.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4385615&req=5

fig1: ERβ1 expression in archival TNBC specimens. Representative examples are shown of IHC staining of tumor and nonmalignant tissue specimens using anti-ERβ1 antibody (AbDSerotec PPG5/10). (a) TNBC specimen shows nuclear (and cytoplasmic) immunostaining of ERβ1 at low magnification. (b) The same TNBC specimen shows nuclear (and cytoplasmic) immunostaining of ERβ1 at higher magnification. (c) Expression of nuclear ERβ1 is also observed in neighboring nonmalignant mammary tissue from the clinical specimen used in panels (a) and (b). (d) Negative ERβ1 detected in a different clinical specimen as shown as comparison. Antibody binding was detected by using the “Envision+” amplification system followed by chromogen detection with diaminobenzidine (DAKO). Sections were counterstained with Harris hematoxylin followed by dehydration through graded alcohol solutions and mounting. See Table 2 for a summary of findings on all TNBC cases examined.
Mentions: Several reports indicate that ERβ expression in node-positive breast cancer is a biomarker for more aggressive disease [8, 21]. For these studies, we used 14 archival TNBC specimens with demographic characteristics including American Joint Committee on Cancer (AJCC) stages provided in Table 1. Using immunohistochemistry, specific ERβ1 staining was observed and scored in nuclear sites, with our observations noted in Table 2. Representative immune staining patterns are shown in Figure 1. Of note, we also observed evidence of diffuse extranuclear ERβ1 staining in most specimens but this staining was not scored or analyzed for this report. In further analyses, we assessed the clinical outcome of 14 patients with a 5-year follow-up whose tumors expressed or did not express ERβ1. In this group of patients with advanced TNBC, overall survival (OS) was significantly worse for TNBC patients with high nuclear ERβ1 (positive) as compared to those with low (negative) ERβ1 (P < 0.001; see Figure 2). Finally, we note that, of the African American patients included in our sample of 14 TNBC patients (11 Caucasian and 3 African American women), all three had tumors that were ERβ1-positive.

Bottom Line: To assess ERβ effects on proliferation, ERβ expression in TNBC cells was silenced using shRNA, resulting in a significant reduction in TNBC proliferation.Growth-stimulating effects of ERβ may be due in part to downstream actions that promote VEGF, amphiregulin, and Wnt-10b secretion, other factors associated with tumor promotion.In vivo, insulin-like growth factor-2 (IGF-2), along with ERβ1, is significantly expressed in TNBC and stimulates high ERβ mRNA in TNBC cells.

View Article: PubMed Central - PubMed

Affiliation: UCLA School of Nursing, Los Angeles, CA 90095, USA ; UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA 90095, USA.

ABSTRACT
Triple-negative breast cancer (TNBC) occurs in 10-15% of patients yet accounts for almost half of all breast cancer deaths. TNBCs lack expression of estrogen and progesterone receptors and HER-2 overexpression and cannot be treated with current targeted therapies. TNBCs often occur in African American and younger women. Although initially responsive to some chemotherapies, TNBCs tend to relapse and metastasize. Thus, it is critical to find new therapeutic targets. A second ER gene product, termed ERβ, in the absence of ERα may be such a target. Using human TNBC specimens with known clinical outcomes to assess ERβ expression, we find that ERβ1 associates with significantly worse 5-year overall survival. Further, a panel of TNBC cell lines exhibit significant levels of ERβ protein. To assess ERβ effects on proliferation, ERβ expression in TNBC cells was silenced using shRNA, resulting in a significant reduction in TNBC proliferation. ERβ-specific antagonists similarly suppressed TNBC growth. Growth-stimulating effects of ERβ may be due in part to downstream actions that promote VEGF, amphiregulin, and Wnt-10b secretion, other factors associated with tumor promotion. In vivo, insulin-like growth factor-2 (IGF-2), along with ERβ1, is significantly expressed in TNBC and stimulates high ERβ mRNA in TNBC cells. This work may help elucidate the interplay of metabolic and growth factors in TNBC.

Show MeSH
Related in: MedlinePlus