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The retinoblastoma tumor suppressor pathway modulates the invasiveness of ErbB2-positive breast cancer.

Witkiewicz AK, Cox DW, Rivadeneira D, Ertel AE, Fortina P, Schwartz GF, Knudsen ES - Oncogene (2013)

Bottom Line: Further, stable knockdown of RB resulted in invasive lesions in orthotopic xenograft assays, compared with DCIS-like lesions developing from RB-proficient cells.Conversely, the invasive phenotype observed in ErbB2-positive cancer models was inhibited through CDK4/6 inhibition in an RB-dependent manner.Taken together, these data demonstrate a key role for the RB pathway in invasion associated with breast tumor progression, and shed light on the key molecular events that promote the progression of DCIS to invasive disease.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA [2] Simmons Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA.

ABSTRACT
The processes that control the progression of ductal carcinoma in situ (DCIS) to invasive breast cancer remain poorly understood. Epidermal growth factor receptor 2 (ErbB2) overexpression is common in DCIS, as is disruption of the retinoblastoma tumor suppressor (RB) pathway. Here, we examined the cooperative impact of ErbB2 and RB deregulation on facets of disease progression. Our studies demonstrate that RB deficiency altered the expression of key molecules needed for proper cellular organization and epithelial cell-cell adhesion as part of a program related to the epithelial-to-mesenchymal transition (EMT). An increase in the invasive potential of ErbB2-overexpressing cells was observed upon RB depletion. Further, stable knockdown of RB resulted in invasive lesions in orthotopic xenograft assays, compared with DCIS-like lesions developing from RB-proficient cells. Conversely, the invasive phenotype observed in ErbB2-positive cancer models was inhibited through CDK4/6 inhibition in an RB-dependent manner. Finally, in a cohort of DCIS cases, we show that, although elevated levels of ErbB2 are associated with increased risk of a subsequent DCIS recurrence, it is not associated with progression to invasive disease. In contrast, RB loss in ErbB2-positive DCIS cases was associated with increased risk for invasive breast cancer. Taken together, these data demonstrate a key role for the RB pathway in invasion associated with breast tumor progression, and shed light on the key molecular events that promote the progression of DCIS to invasive disease.

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RB deficiency is associated with increased disease progression in DCIS(A) ErbB2 high (3+) status was compared against all other ErbB2 staining (0, 1+, 2+) for any recurrent disease (ipsilateral breast event) or invasive progression using Kaplan-Meier analysis. ErbB2 high was associated with risk of a subsequent ipsilateral breast event, but not progression to invasive disease. (B) Representative images of RB staining in DCIS lesions cases with high ErbB2. (C) ErbB2 high (3+) cases were stratified by RB status (positive vs. negative). Cases with RB loss in this subtype were associated with both risk of a subsequent ipsilateral breast event and progression to invasive disease.
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Figure 7: RB deficiency is associated with increased disease progression in DCIS(A) ErbB2 high (3+) status was compared against all other ErbB2 staining (0, 1+, 2+) for any recurrent disease (ipsilateral breast event) or invasive progression using Kaplan-Meier analysis. ErbB2 high was associated with risk of a subsequent ipsilateral breast event, but not progression to invasive disease. (B) Representative images of RB staining in DCIS lesions cases with high ErbB2. (C) ErbB2 high (3+) cases were stratified by RB status (positive vs. negative). Cases with RB loss in this subtype were associated with both risk of a subsequent ipsilateral breast event and progression to invasive disease.

Mentions: The observation that RB-deficiency is associated with enhanced invasive properties and cooperated with ErbB2 over expression, supported a combined role for the two pathways in DCIS progression. We employed a cohort of 226 cases of DCIS for which ErbB2 and RB status were determined. These patient that were treated with surgery in the absence of adjuvant therapy, with long-term followup (median 8.6 years)(26). This cohort provides the opportunity to specifically evaluate prognostic markers of ipsilateral breast events or invasive progression. Optimized staining for ErB2 and RB was performed (representative images, Figure 7A). Consistent with other studies (41), elevated ErbB2 expression (3+ staining) is observed in DCIS and is associated with a modest increase in risk for subsequent DCIS recurrence (Figure 7B). However, overexpression of ErbB2 is not associated with increased risk for invasion (p>0.05). In ErbB2-positive DCIS, histochemical RB loss was observed in approximately 25 percent of cases. In this setting RB loss was associated with a further increased risk for recurrence within ErbB2-positive and importantly was also significantly associated with progression to invasive breast cancer (Figure 7C). These data, suggest that loss of RB can contribute to the function of ErbB2 in driving disease progression.


The retinoblastoma tumor suppressor pathway modulates the invasiveness of ErbB2-positive breast cancer.

Witkiewicz AK, Cox DW, Rivadeneira D, Ertel AE, Fortina P, Schwartz GF, Knudsen ES - Oncogene (2013)

RB deficiency is associated with increased disease progression in DCIS(A) ErbB2 high (3+) status was compared against all other ErbB2 staining (0, 1+, 2+) for any recurrent disease (ipsilateral breast event) or invasive progression using Kaplan-Meier analysis. ErbB2 high was associated with risk of a subsequent ipsilateral breast event, but not progression to invasive disease. (B) Representative images of RB staining in DCIS lesions cases with high ErbB2. (C) ErbB2 high (3+) cases were stratified by RB status (positive vs. negative). Cases with RB loss in this subtype were associated with both risk of a subsequent ipsilateral breast event and progression to invasive disease.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4150690&req=5

Figure 7: RB deficiency is associated with increased disease progression in DCIS(A) ErbB2 high (3+) status was compared against all other ErbB2 staining (0, 1+, 2+) for any recurrent disease (ipsilateral breast event) or invasive progression using Kaplan-Meier analysis. ErbB2 high was associated with risk of a subsequent ipsilateral breast event, but not progression to invasive disease. (B) Representative images of RB staining in DCIS lesions cases with high ErbB2. (C) ErbB2 high (3+) cases were stratified by RB status (positive vs. negative). Cases with RB loss in this subtype were associated with both risk of a subsequent ipsilateral breast event and progression to invasive disease.
Mentions: The observation that RB-deficiency is associated with enhanced invasive properties and cooperated with ErbB2 over expression, supported a combined role for the two pathways in DCIS progression. We employed a cohort of 226 cases of DCIS for which ErbB2 and RB status were determined. These patient that were treated with surgery in the absence of adjuvant therapy, with long-term followup (median 8.6 years)(26). This cohort provides the opportunity to specifically evaluate prognostic markers of ipsilateral breast events or invasive progression. Optimized staining for ErB2 and RB was performed (representative images, Figure 7A). Consistent with other studies (41), elevated ErbB2 expression (3+ staining) is observed in DCIS and is associated with a modest increase in risk for subsequent DCIS recurrence (Figure 7B). However, overexpression of ErbB2 is not associated with increased risk for invasion (p>0.05). In ErbB2-positive DCIS, histochemical RB loss was observed in approximately 25 percent of cases. In this setting RB loss was associated with a further increased risk for recurrence within ErbB2-positive and importantly was also significantly associated with progression to invasive breast cancer (Figure 7C). These data, suggest that loss of RB can contribute to the function of ErbB2 in driving disease progression.

Bottom Line: Further, stable knockdown of RB resulted in invasive lesions in orthotopic xenograft assays, compared with DCIS-like lesions developing from RB-proficient cells.Conversely, the invasive phenotype observed in ErbB2-positive cancer models was inhibited through CDK4/6 inhibition in an RB-dependent manner.Taken together, these data demonstrate a key role for the RB pathway in invasion associated with breast tumor progression, and shed light on the key molecular events that promote the progression of DCIS to invasive disease.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA [2] Simmons Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA.

ABSTRACT
The processes that control the progression of ductal carcinoma in situ (DCIS) to invasive breast cancer remain poorly understood. Epidermal growth factor receptor 2 (ErbB2) overexpression is common in DCIS, as is disruption of the retinoblastoma tumor suppressor (RB) pathway. Here, we examined the cooperative impact of ErbB2 and RB deregulation on facets of disease progression. Our studies demonstrate that RB deficiency altered the expression of key molecules needed for proper cellular organization and epithelial cell-cell adhesion as part of a program related to the epithelial-to-mesenchymal transition (EMT). An increase in the invasive potential of ErbB2-overexpressing cells was observed upon RB depletion. Further, stable knockdown of RB resulted in invasive lesions in orthotopic xenograft assays, compared with DCIS-like lesions developing from RB-proficient cells. Conversely, the invasive phenotype observed in ErbB2-positive cancer models was inhibited through CDK4/6 inhibition in an RB-dependent manner. Finally, in a cohort of DCIS cases, we show that, although elevated levels of ErbB2 are associated with increased risk of a subsequent DCIS recurrence, it is not associated with progression to invasive disease. In contrast, RB loss in ErbB2-positive DCIS cases was associated with increased risk for invasive breast cancer. Taken together, these data demonstrate a key role for the RB pathway in invasion associated with breast tumor progression, and shed light on the key molecular events that promote the progression of DCIS to invasive disease.

Show MeSH
Related in: MedlinePlus