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Folate receptor-α (FOLR1) expression and function in triple negative tumors.

Necela BM, Crozier JA, Andorfer CA, Lewis-Tuffin L, Kachergus JM, Geiger XJ, Kalari KR, Serie DJ, Sun Z, Moreno-Aspitia A, Aspita AM, O'Shannessy DJ, Maltzman JD, McCullough AE, Pockaj BA, Cunliffe HE, Ballman KV, Thompson EA, Perez EA - PLoS ONE (2015)

Bottom Line: FOLR1 expression varied within breast tumor subtypes; triple negative/basal tumors were significantly associated with increased expression of FOLR1 mRNA, compared to ER+ and HER2+ tumors.FOLR1 expression did not correlate to common clinicopathological parameters such as tumor stage and nodal status.Loss of FOLR1 resulted in growth inhibition, whereas FOLR1 overexpression promoted folate uptake and growth advantage in low folate conditions.

View Article: PubMed Central - PubMed

Affiliation: Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, United Sates of America.

ABSTRACT
Folate receptor alpha (FOLR1) has been identified as a potential prognostic and therapeutic target in a number of cancers. A correlation has been shown between intense overexpression of FOLR1 in breast tumors and poor prognosis, yet there is limited examination of the distribution of FOLR1 across clinically relevant breast cancer subtypes. To explore this further, we used RNA-seq data from multiple patient cohorts to analyze the distribution of FOLR1 mRNA across breast cancer subtypes comprised of estrogen receptor positive (ER+), human epidermal growth factor receptor positive (HER2+), and triple negative (TNBC) tumors. FOLR1 expression varied within breast tumor subtypes; triple negative/basal tumors were significantly associated with increased expression of FOLR1 mRNA, compared to ER+ and HER2+ tumors. However, subsets of high level FOLR1 expressing tumors were observed in all clinical subtypes. These observations were supported by immunohistochemical analysis of tissue microarrays, with the largest number of 3+ positive tumors and highest H-scores of any subtype represented by triple negatives, and lowest by ER+ tumors. FOLR1 expression did not correlate to common clinicopathological parameters such as tumor stage and nodal status. To delineate the importance of FOLR1 overexpression in triple negative cancers, RNA-interference was used to deplete FOLR1 in overexpressing triple negative cell breast lines. Loss of FOLR1 resulted in growth inhibition, whereas FOLR1 overexpression promoted folate uptake and growth advantage in low folate conditions. Taken together, our data suggests patients with triple negative cancers expressing high FOLR1 expression represent an important population of patients that may benefit from targeted anti-FOLR1 therapy. This may prove particularly helpful for a large number of patients who would typically be classified as triple negative and who to this point have been left without any targeted treatment options.

No MeSH data available.


Related in: MedlinePlus

Representative FOLR1 staining from breast cancer subtypes.(A) benign breast tissue (B9) with negative staining (IHC score 0), (B) estrogen receptor positive invasive ductal carcinoma (ER+IDC) with negative staining (IHC score 0), (C) estrogen receptor positive invasive lobular carcinoma (ER+ILC) with negative staining (IHC score 0), (D) human epidermal growth factor receptor positive (HER2+) with strong 3+ staining (left core) and weak 1+ staining (middle/right cores), and (E) triple negative (TNBC) tumors with strong 3+ staining (left core) and moderate 2+ staining (middle/right cores).
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pone.0122209.g003: Representative FOLR1 staining from breast cancer subtypes.(A) benign breast tissue (B9) with negative staining (IHC score 0), (B) estrogen receptor positive invasive ductal carcinoma (ER+IDC) with negative staining (IHC score 0), (C) estrogen receptor positive invasive lobular carcinoma (ER+ILC) with negative staining (IHC score 0), (D) human epidermal growth factor receptor positive (HER2+) with strong 3+ staining (left core) and weak 1+ staining (middle/right cores), and (E) triple negative (TNBC) tumors with strong 3+ staining (left core) and moderate 2+ staining (middle/right cores).

Mentions: Competing Interests: The authors confirm that “Daniel J. O’Shannessy and Julia D. Maltzman are employees of Morphotek, developers of the FOLR1 antibody farletuzumab and as such have received support in the form of salaries from Morphotek. Daniel J. O’Shannessy and Julia D. Maltzman did not have any additional role in the data collection and analysis, manuscript preparation or decision to publish. However, both were involved in minor aspects of study design by providing protocols and technical advice on staining tissues for folate receptor expression (Fig. 3). Data collection, data interpretation, manuscript preparation and the decision to publish resided exclusively with Mayo Clinic investigators. The inclusion of Daniel J. O’Shannessy and Julia D. Maltzman as coauthors does not alter the authors' adherence to PLOS One policies on sharing data and materials.


Folate receptor-α (FOLR1) expression and function in triple negative tumors.

Necela BM, Crozier JA, Andorfer CA, Lewis-Tuffin L, Kachergus JM, Geiger XJ, Kalari KR, Serie DJ, Sun Z, Moreno-Aspitia A, Aspita AM, O'Shannessy DJ, Maltzman JD, McCullough AE, Pockaj BA, Cunliffe HE, Ballman KV, Thompson EA, Perez EA - PLoS ONE (2015)

Representative FOLR1 staining from breast cancer subtypes.(A) benign breast tissue (B9) with negative staining (IHC score 0), (B) estrogen receptor positive invasive ductal carcinoma (ER+IDC) with negative staining (IHC score 0), (C) estrogen receptor positive invasive lobular carcinoma (ER+ILC) with negative staining (IHC score 0), (D) human epidermal growth factor receptor positive (HER2+) with strong 3+ staining (left core) and weak 1+ staining (middle/right cores), and (E) triple negative (TNBC) tumors with strong 3+ staining (left core) and moderate 2+ staining (middle/right cores).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4376802&req=5

pone.0122209.g003: Representative FOLR1 staining from breast cancer subtypes.(A) benign breast tissue (B9) with negative staining (IHC score 0), (B) estrogen receptor positive invasive ductal carcinoma (ER+IDC) with negative staining (IHC score 0), (C) estrogen receptor positive invasive lobular carcinoma (ER+ILC) with negative staining (IHC score 0), (D) human epidermal growth factor receptor positive (HER2+) with strong 3+ staining (left core) and weak 1+ staining (middle/right cores), and (E) triple negative (TNBC) tumors with strong 3+ staining (left core) and moderate 2+ staining (middle/right cores).
Mentions: Competing Interests: The authors confirm that “Daniel J. O’Shannessy and Julia D. Maltzman are employees of Morphotek, developers of the FOLR1 antibody farletuzumab and as such have received support in the form of salaries from Morphotek. Daniel J. O’Shannessy and Julia D. Maltzman did not have any additional role in the data collection and analysis, manuscript preparation or decision to publish. However, both were involved in minor aspects of study design by providing protocols and technical advice on staining tissues for folate receptor expression (Fig. 3). Data collection, data interpretation, manuscript preparation and the decision to publish resided exclusively with Mayo Clinic investigators. The inclusion of Daniel J. O’Shannessy and Julia D. Maltzman as coauthors does not alter the authors' adherence to PLOS One policies on sharing data and materials.

Bottom Line: FOLR1 expression varied within breast tumor subtypes; triple negative/basal tumors were significantly associated with increased expression of FOLR1 mRNA, compared to ER+ and HER2+ tumors.FOLR1 expression did not correlate to common clinicopathological parameters such as tumor stage and nodal status.Loss of FOLR1 resulted in growth inhibition, whereas FOLR1 overexpression promoted folate uptake and growth advantage in low folate conditions.

View Article: PubMed Central - PubMed

Affiliation: Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, United Sates of America.

ABSTRACT
Folate receptor alpha (FOLR1) has been identified as a potential prognostic and therapeutic target in a number of cancers. A correlation has been shown between intense overexpression of FOLR1 in breast tumors and poor prognosis, yet there is limited examination of the distribution of FOLR1 across clinically relevant breast cancer subtypes. To explore this further, we used RNA-seq data from multiple patient cohorts to analyze the distribution of FOLR1 mRNA across breast cancer subtypes comprised of estrogen receptor positive (ER+), human epidermal growth factor receptor positive (HER2+), and triple negative (TNBC) tumors. FOLR1 expression varied within breast tumor subtypes; triple negative/basal tumors were significantly associated with increased expression of FOLR1 mRNA, compared to ER+ and HER2+ tumors. However, subsets of high level FOLR1 expressing tumors were observed in all clinical subtypes. These observations were supported by immunohistochemical analysis of tissue microarrays, with the largest number of 3+ positive tumors and highest H-scores of any subtype represented by triple negatives, and lowest by ER+ tumors. FOLR1 expression did not correlate to common clinicopathological parameters such as tumor stage and nodal status. To delineate the importance of FOLR1 overexpression in triple negative cancers, RNA-interference was used to deplete FOLR1 in overexpressing triple negative cell breast lines. Loss of FOLR1 resulted in growth inhibition, whereas FOLR1 overexpression promoted folate uptake and growth advantage in low folate conditions. Taken together, our data suggests patients with triple negative cancers expressing high FOLR1 expression represent an important population of patients that may benefit from targeted anti-FOLR1 therapy. This may prove particularly helpful for a large number of patients who would typically be classified as triple negative and who to this point have been left without any targeted treatment options.

No MeSH data available.


Related in: MedlinePlus