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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.

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IGF-2 and ERβ1 are highly expressed in TNBC tumors. Archival breast tissue from patients with TNBC along with adjacent normal tissue adjacent to TNBC tumors was obtained from the NIH CHTN and UCLA Early Detection Research Network. Immunohistological assays were used to evaluate tissue samples for IGF-2 and ERβ1 expression (see Section 2). (a) Representation of IGF-2 and ERβ1 expression in normal and TNBC breast tissue. IGF-2 (A and B) and ERβ1 (C and D) expression were evaluated and visualized using Evos xl Core microscope. Representative images are presented. (b) Allred scoring of IGF-2 and ERβ1 in archival breast tissue. Samples from neighboring normal tissue (n = 7) and from TNBC tumors (n = 11) were stained for IGF-2 and ERβ1 then scored using Allred-based criterion (see Section 2). IGF-2 (**P < 0.01) and ERβ1 (***P < 0.005) were notably expressed in TNBC tumor samples. Statistical significance was determined using Student's t-test (Graphpad). Error bars: SE.
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fig9: IGF-2 and ERβ1 are highly expressed in TNBC tumors. Archival breast tissue from patients with TNBC along with adjacent normal tissue adjacent to TNBC tumors was obtained from the NIH CHTN and UCLA Early Detection Research Network. Immunohistological assays were used to evaluate tissue samples for IGF-2 and ERβ1 expression (see Section 2). (a) Representation of IGF-2 and ERβ1 expression in normal and TNBC breast tissue. IGF-2 (A and B) and ERβ1 (C and D) expression were evaluated and visualized using Evos xl Core microscope. Representative images are presented. (b) Allred scoring of IGF-2 and ERβ1 in archival breast tissue. Samples from neighboring normal tissue (n = 7) and from TNBC tumors (n = 11) were stained for IGF-2 and ERβ1 then scored using Allred-based criterion (see Section 2). IGF-2 (**P < 0.01) and ERβ1 (***P < 0.005) were notably expressed in TNBC tumor samples. Statistical significance was determined using Student's t-test (Graphpad). Error bars: SE.

Mentions: Since the expression of IGF-2 and ERβ1 is associated with poor patient outcomes, we evaluated their coexpression in normal breast tissue and TNBC tumors (Figure 9). Using immunohistochemistry, archival TNBC tumors and adjacent nonmalignant breast specimens were evaluated for IGF-2 and ERβ1 expression (Figure 9(a)). In the samples evaluated and scored, notably increased expression of IGF-2 (P < 0.01) and ERβ1 (P < 0.005) is found in all TNBC tumors examined (Figure 9(b)).


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)

IGF-2 and ERβ1 are highly expressed in TNBC tumors. Archival breast tissue from patients with TNBC along with adjacent normal tissue adjacent to TNBC tumors was obtained from the NIH CHTN and UCLA Early Detection Research Network. Immunohistological assays were used to evaluate tissue samples for IGF-2 and ERβ1 expression (see Section 2). (a) Representation of IGF-2 and ERβ1 expression in normal and TNBC breast tissue. IGF-2 (A and B) and ERβ1 (C and D) expression were evaluated and visualized using Evos xl Core microscope. Representative images are presented. (b) Allred scoring of IGF-2 and ERβ1 in archival breast tissue. Samples from neighboring normal tissue (n = 7) and from TNBC tumors (n = 11) were stained for IGF-2 and ERβ1 then scored using Allred-based criterion (see Section 2). IGF-2 (**P < 0.01) and ERβ1 (***P < 0.005) were notably expressed in TNBC tumor samples. Statistical significance was determined using Student's t-test (Graphpad). Error bars: SE.
© Copyright Policy
Related In: Results  -  Collection

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

fig9: IGF-2 and ERβ1 are highly expressed in TNBC tumors. Archival breast tissue from patients with TNBC along with adjacent normal tissue adjacent to TNBC tumors was obtained from the NIH CHTN and UCLA Early Detection Research Network. Immunohistological assays were used to evaluate tissue samples for IGF-2 and ERβ1 expression (see Section 2). (a) Representation of IGF-2 and ERβ1 expression in normal and TNBC breast tissue. IGF-2 (A and B) and ERβ1 (C and D) expression were evaluated and visualized using Evos xl Core microscope. Representative images are presented. (b) Allred scoring of IGF-2 and ERβ1 in archival breast tissue. Samples from neighboring normal tissue (n = 7) and from TNBC tumors (n = 11) were stained for IGF-2 and ERβ1 then scored using Allred-based criterion (see Section 2). IGF-2 (**P < 0.01) and ERβ1 (***P < 0.005) were notably expressed in TNBC tumor samples. Statistical significance was determined using Student's t-test (Graphpad). Error bars: SE.
Mentions: Since the expression of IGF-2 and ERβ1 is associated with poor patient outcomes, we evaluated their coexpression in normal breast tissue and TNBC tumors (Figure 9). Using immunohistochemistry, archival TNBC tumors and adjacent nonmalignant breast specimens were evaluated for IGF-2 and ERβ1 expression (Figure 9(a)). In the samples evaluated and scored, notably increased expression of IGF-2 (P < 0.01) and ERβ1 (P < 0.005) is found in all TNBC tumors examined (Figure 9(b)).

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