Postlactational involution biomarkers plasminogen and phospho-STAT3 are linked with active age-related lobular involution

Melody L. Stallings-Mann, Ethan P. Heinzen, Robert A. Vierkant, Stacey J Winham, Tanya L. Hoskin, Lori A. Denison, Aziza Nassar, Lynn C. Hartmann, Daniel W Visscher, Marlene H. Frost, Mark E. Sherman, Amy C Degnim, Derek C Radisky

Research output: Contribution to journalArticle

Abstract

Purpose: Breast terminal duct lobular units undergo two distinctive physiological processes of involution: age-related lobular involution (LI), which is gradual and associated with decreased breast cancer risk, and postlactational involution, which is relatively precipitous, occurs with weaning, and has been associated with potentiation of tumor aggressiveness in animal models. Here we assessed whether markers of postlactational involution are associated with ongoing LI in a retrospective tissue cohort. Methods: We selected 57 women from the Mayo Clinic Benign Breast Disease Cohort who underwent multiple biopsies and who were average age 48 at initial biopsy. Women were classified as having progressive or non-progressive LI between initial and subsequent biopsy. Serial tissue sections were immunostained for plasminogen, matrix metalloproteinase 9 (MMP-9), phospho-STAT3 (pSTAT3), tenascin C, Ki67, CD44, cytokeratin 14 (CK14), cytokeratin 19 (CK19), and c-myc. All but Ki67 were digitally quantified. Associations between maximal marker expression per sample and progressive versus non-progressive LI were assessed using logistic regression and adjusted for potential confounders. Results: While no biomarker showed statistically significant association with LI progression when evaluated individually, lower expression of pSTAT3 (OR 0.35, 95% CI 0.13–0.82, p = 0.01) and higher expression of plasminogen (OR 2.89, 95% CI 1.14–8.81, p = 0.02) were associated with progressive LI in models simultaneously adjusted for all biomarkers. Sensitivity analyses indicated that the strengthening in association for pSTAT3 and plasminogen with progressive LI was due to collinearity between these two markers. Conclusions: This is the first study to identify biomarkers of active LI. Our findings that plasminogen and pSTAT3 are significantly associated with LI suggest that they may represent signaling nodes or biomarkers of pathways common to the processes of postlactational involution and LI.

Original languageEnglish (US)
Pages (from-to)1-11
Number of pages11
JournalBreast Cancer Research and Treatment
DOIs
StateAccepted/In press - Jul 27 2017

Fingerprint

Plasminogen
Biomarkers
Biopsy
Keratin-14
Physiological Phenomena
Keratin-19
Tenascin
Breast Diseases
Matrix Metalloproteinase 9
Weaning
Breast
Animal Models
Logistic Models
Breast Neoplasms
Neoplasms

Keywords

  • Biomarkers
  • Breast cancer
  • Cohort studies
  • Lobular involution
  • Postlactational involution

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Postlactational involution biomarkers plasminogen and phospho-STAT3 are linked with active age-related lobular involution. / Stallings-Mann, Melody L.; Heinzen, Ethan P.; Vierkant, Robert A.; Winham, Stacey J; Hoskin, Tanya L.; Denison, Lori A.; Nassar, Aziza; Hartmann, Lynn C.; Visscher, Daniel W; Frost, Marlene H.; Sherman, Mark E.; Degnim, Amy C; Radisky, Derek C.

In: Breast Cancer Research and Treatment, 27.07.2017, p. 1-11.

Research output: Contribution to journalArticle

Stallings-Mann, Melody L. ; Heinzen, Ethan P. ; Vierkant, Robert A. ; Winham, Stacey J ; Hoskin, Tanya L. ; Denison, Lori A. ; Nassar, Aziza ; Hartmann, Lynn C. ; Visscher, Daniel W ; Frost, Marlene H. ; Sherman, Mark E. ; Degnim, Amy C ; Radisky, Derek C. / Postlactational involution biomarkers plasminogen and phospho-STAT3 are linked with active age-related lobular involution. In: Breast Cancer Research and Treatment. 2017 ; pp. 1-11.
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abstract = "Purpose: Breast terminal duct lobular units undergo two distinctive physiological processes of involution: age-related lobular involution (LI), which is gradual and associated with decreased breast cancer risk, and postlactational involution, which is relatively precipitous, occurs with weaning, and has been associated with potentiation of tumor aggressiveness in animal models. Here we assessed whether markers of postlactational involution are associated with ongoing LI in a retrospective tissue cohort. Methods: We selected 57 women from the Mayo Clinic Benign Breast Disease Cohort who underwent multiple biopsies and who were average age 48 at initial biopsy. Women were classified as having progressive or non-progressive LI between initial and subsequent biopsy. Serial tissue sections were immunostained for plasminogen, matrix metalloproteinase 9 (MMP-9), phospho-STAT3 (pSTAT3), tenascin C, Ki67, CD44, cytokeratin 14 (CK14), cytokeratin 19 (CK19), and c-myc. All but Ki67 were digitally quantified. Associations between maximal marker expression per sample and progressive versus non-progressive LI were assessed using logistic regression and adjusted for potential confounders. Results: While no biomarker showed statistically significant association with LI progression when evaluated individually, lower expression of pSTAT3 (OR 0.35, 95{\%} CI 0.13–0.82, p = 0.01) and higher expression of plasminogen (OR 2.89, 95{\%} CI 1.14–8.81, p = 0.02) were associated with progressive LI in models simultaneously adjusted for all biomarkers. Sensitivity analyses indicated that the strengthening in association for pSTAT3 and plasminogen with progressive LI was due to collinearity between these two markers. Conclusions: This is the first study to identify biomarkers of active LI. Our findings that plasminogen and pSTAT3 are significantly associated with LI suggest that they may represent signaling nodes or biomarkers of pathways common to the processes of postlactational involution and LI.",
keywords = "Biomarkers, Breast cancer, Cohort studies, Lobular involution, Postlactational involution",
author = "Stallings-Mann, {Melody L.} and Heinzen, {Ethan P.} and Vierkant, {Robert A.} and Winham, {Stacey J} and Hoskin, {Tanya L.} and Denison, {Lori A.} and Aziza Nassar and Hartmann, {Lynn C.} and Visscher, {Daniel W} and Frost, {Marlene H.} and Sherman, {Mark E.} and Degnim, {Amy C} and Radisky, {Derek C}",
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T1 - Postlactational involution biomarkers plasminogen and phospho-STAT3 are linked with active age-related lobular involution

AU - Stallings-Mann, Melody L.

AU - Heinzen, Ethan P.

AU - Vierkant, Robert A.

AU - Winham, Stacey J

AU - Hoskin, Tanya L.

AU - Denison, Lori A.

AU - Nassar, Aziza

AU - Hartmann, Lynn C.

AU - Visscher, Daniel W

AU - Frost, Marlene H.

AU - Sherman, Mark E.

AU - Degnim, Amy C

AU - Radisky, Derek C

PY - 2017/7/27

Y1 - 2017/7/27

N2 - Purpose: Breast terminal duct lobular units undergo two distinctive physiological processes of involution: age-related lobular involution (LI), which is gradual and associated with decreased breast cancer risk, and postlactational involution, which is relatively precipitous, occurs with weaning, and has been associated with potentiation of tumor aggressiveness in animal models. Here we assessed whether markers of postlactational involution are associated with ongoing LI in a retrospective tissue cohort. Methods: We selected 57 women from the Mayo Clinic Benign Breast Disease Cohort who underwent multiple biopsies and who were average age 48 at initial biopsy. Women were classified as having progressive or non-progressive LI between initial and subsequent biopsy. Serial tissue sections were immunostained for plasminogen, matrix metalloproteinase 9 (MMP-9), phospho-STAT3 (pSTAT3), tenascin C, Ki67, CD44, cytokeratin 14 (CK14), cytokeratin 19 (CK19), and c-myc. All but Ki67 were digitally quantified. Associations between maximal marker expression per sample and progressive versus non-progressive LI were assessed using logistic regression and adjusted for potential confounders. Results: While no biomarker showed statistically significant association with LI progression when evaluated individually, lower expression of pSTAT3 (OR 0.35, 95% CI 0.13–0.82, p = 0.01) and higher expression of plasminogen (OR 2.89, 95% CI 1.14–8.81, p = 0.02) were associated with progressive LI in models simultaneously adjusted for all biomarkers. Sensitivity analyses indicated that the strengthening in association for pSTAT3 and plasminogen with progressive LI was due to collinearity between these two markers. Conclusions: This is the first study to identify biomarkers of active LI. Our findings that plasminogen and pSTAT3 are significantly associated with LI suggest that they may represent signaling nodes or biomarkers of pathways common to the processes of postlactational involution and LI.

AB - Purpose: Breast terminal duct lobular units undergo two distinctive physiological processes of involution: age-related lobular involution (LI), which is gradual and associated with decreased breast cancer risk, and postlactational involution, which is relatively precipitous, occurs with weaning, and has been associated with potentiation of tumor aggressiveness in animal models. Here we assessed whether markers of postlactational involution are associated with ongoing LI in a retrospective tissue cohort. Methods: We selected 57 women from the Mayo Clinic Benign Breast Disease Cohort who underwent multiple biopsies and who were average age 48 at initial biopsy. Women were classified as having progressive or non-progressive LI between initial and subsequent biopsy. Serial tissue sections were immunostained for plasminogen, matrix metalloproteinase 9 (MMP-9), phospho-STAT3 (pSTAT3), tenascin C, Ki67, CD44, cytokeratin 14 (CK14), cytokeratin 19 (CK19), and c-myc. All but Ki67 were digitally quantified. Associations between maximal marker expression per sample and progressive versus non-progressive LI were assessed using logistic regression and adjusted for potential confounders. Results: While no biomarker showed statistically significant association with LI progression when evaluated individually, lower expression of pSTAT3 (OR 0.35, 95% CI 0.13–0.82, p = 0.01) and higher expression of plasminogen (OR 2.89, 95% CI 1.14–8.81, p = 0.02) were associated with progressive LI in models simultaneously adjusted for all biomarkers. Sensitivity analyses indicated that the strengthening in association for pSTAT3 and plasminogen with progressive LI was due to collinearity between these two markers. Conclusions: This is the first study to identify biomarkers of active LI. Our findings that plasminogen and pSTAT3 are significantly associated with LI suggest that they may represent signaling nodes or biomarkers of pathways common to the processes of postlactational involution and LI.

KW - Biomarkers

KW - Breast cancer

KW - Cohort studies

KW - Lobular involution

KW - Postlactational involution

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