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

High levels of IGF-2 occur in archival TNBC tumors as compared to ERα+ and ERα− breast cancers. Archival breast tissues from patients with ERα-positive (ER+, n = 5), ERα-negative (ER−, n = 5), and TNBC (n = 5) breast cancer were evaluated for IGF-2 expression. Validated IHC staining methods were used to evaluate IGF-2 expression in tumor epithelium (a) and neighboring stroma (b). Scoring was done using an Allred-based criterion. (a) Significantly higher expression of IGF-2 is found in the epithelium of TNBC tumors as compared to ER+ (**P < 0.01) and ER− breast cancers (**P < 0.01). (b) Compared to ER+ and ER− archival breast tumors, stromal tissue adjacent to TNBC tumors expressed significantly higher levels of IGF-2 than stromal tissue neighboring non-TNBCs (**P < 0.01 and *P < 0.05 for ER+ and ER−, resp.). Error bars: SD.
© Copyright Policy
Related In: Results  -  Collection

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

fig8: High levels of IGF-2 occur in archival TNBC tumors as compared to ERα+ and ERα− breast cancers. Archival breast tissues from patients with ERα-positive (ER+, n = 5), ERα-negative (ER−, n = 5), and TNBC (n = 5) breast cancer were evaluated for IGF-2 expression. Validated IHC staining methods were used to evaluate IGF-2 expression in tumor epithelium (a) and neighboring stroma (b). Scoring was done using an Allred-based criterion. (a) Significantly higher expression of IGF-2 is found in the epithelium of TNBC tumors as compared to ER+ (**P < 0.01) and ER− breast cancers (**P < 0.01). (b) Compared to ER+ and ER− archival breast tumors, stromal tissue adjacent to TNBC tumors expressed significantly higher levels of IGF-2 than stromal tissue neighboring non-TNBCs (**P < 0.01 and *P < 0.05 for ER+ and ER−, resp.). Error bars: SD.

Mentions: IGF-2 is a secreted protein highly expressed in breast tumor tissue. To assess the association of elevated IGF-2 with a specific tumor subtype, we evaluated IGF-2 expression levels in epithelial and neighboring stromal components of ERα-positive (ER+), ERα-negative (ER−), and TNBC tumors. Following pathology review, we obtained archival tissue from 5 patients in each subtype. The patients selected ranged in age from 35 to 61 years (average age 50) with additional demographic characteristics shown in Table 3. In comparison to ER+ and ER− epithelium, TNBC epithelia expressed significantly higher levels of IGF-2 (P < 0.01; see Figure 8(a)). Additionally, IGF-2 staining in neighboring stromal cells was highest in TNBCs as compared to ER− tumors (P = 0.05) and ER+ tumors (P < 0.01; see Figure 8(b)). These results support a potential apocrine and/or paracrine role of IGF-2 in cancer progression.


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)

High levels of IGF-2 occur in archival TNBC tumors as compared to ERα+ and ERα− breast cancers. Archival breast tissues from patients with ERα-positive (ER+, n = 5), ERα-negative (ER−, n = 5), and TNBC (n = 5) breast cancer were evaluated for IGF-2 expression. Validated IHC staining methods were used to evaluate IGF-2 expression in tumor epithelium (a) and neighboring stroma (b). Scoring was done using an Allred-based criterion. (a) Significantly higher expression of IGF-2 is found in the epithelium of TNBC tumors as compared to ER+ (**P < 0.01) and ER− breast cancers (**P < 0.01). (b) Compared to ER+ and ER− archival breast tumors, stromal tissue adjacent to TNBC tumors expressed significantly higher levels of IGF-2 than stromal tissue neighboring non-TNBCs (**P < 0.01 and *P < 0.05 for ER+ and ER−, resp.). Error bars: SD.
© Copyright Policy
Related In: Results  -  Collection

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

fig8: High levels of IGF-2 occur in archival TNBC tumors as compared to ERα+ and ERα− breast cancers. Archival breast tissues from patients with ERα-positive (ER+, n = 5), ERα-negative (ER−, n = 5), and TNBC (n = 5) breast cancer were evaluated for IGF-2 expression. Validated IHC staining methods were used to evaluate IGF-2 expression in tumor epithelium (a) and neighboring stroma (b). Scoring was done using an Allred-based criterion. (a) Significantly higher expression of IGF-2 is found in the epithelium of TNBC tumors as compared to ER+ (**P < 0.01) and ER− breast cancers (**P < 0.01). (b) Compared to ER+ and ER− archival breast tumors, stromal tissue adjacent to TNBC tumors expressed significantly higher levels of IGF-2 than stromal tissue neighboring non-TNBCs (**P < 0.01 and *P < 0.05 for ER+ and ER−, resp.). Error bars: SD.
Mentions: IGF-2 is a secreted protein highly expressed in breast tumor tissue. To assess the association of elevated IGF-2 with a specific tumor subtype, we evaluated IGF-2 expression levels in epithelial and neighboring stromal components of ERα-positive (ER+), ERα-negative (ER−), and TNBC tumors. Following pathology review, we obtained archival tissue from 5 patients in each subtype. The patients selected ranged in age from 35 to 61 years (average age 50) with additional demographic characteristics shown in Table 3. In comparison to ER+ and ER− epithelium, TNBC epithelia expressed significantly higher levels of IGF-2 (P < 0.01; see Figure 8(a)). Additionally, IGF-2 staining in neighboring stromal cells was highest in TNBCs as compared to ER− tumors (P = 0.05) and ER+ tumors (P < 0.01; see Figure 8(b)). These results support a potential apocrine and/or paracrine role of IGF-2 in cancer progression.

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